Novel 2-hydroxytetrahydrofurane derivatives and use thereof as medicaments

ABSTRACT

A hydroxytetrahydrofuran of formula  
                 
 
wherein A is  
                 
with the substituents as defined in the specification, having a calpain inhibiting activity and/or an activity which traps the reactive oxygen species useful for treating inflammatory and immunological diseases, cardio-vascular and cerebro-vascular diseases, disorders of the central or peripheral nervous system, osteoporosis, muscular dystrophy, proliferative diseases, cataract, rejection reactions following organ transplants and autoimmune and viral diseases.

The present invention relates to novel derivatives of2-hydroxytetrahydrofuran having a calpain inhibiting activity and/or anactivity which traps the reactive oxygen species (ROS). The inventionalso relates to their preparation methods, the pharmaceuticalpreparations containing them and their use for therapeutic purposes, inparticular as calpain inhibitors and traps for reactive oxygen speciesin a selective or non-selective manner.

Given the potential role of calpains and ROS's in physiopathology, thenovel derivatives according to the invention can produce beneficial orfavourable effects in the treatment of pathologies where these enzymesand/or these radical species are involved, and in particular:

-   -   inflammatory and immunological diseases such as for example        rheumatoid arthritis, pancreatitis, multiple sclerosis,        inflammations of the gastro-intestinal system (ulcerative or        non-ulcerative colitis, Crohn's disease),    -   cardiovascular and cerebrovascular diseases including for        example arterial hypertension, septic shock, cardiac or cerebral        infarctions of ischaemic or haemorrhagic origin, ischaemias as        well as disorders linked to platelet aggregation,    -   disorders of the central or peripheral nervous system such as        for example neurodegenerative diseases where there can in        particular be mentioned cerebral or spinal cord trauma,        sub-arachnoid haemorrhage, epilepsy, ageing, senile dementia        including Alzheimer's disease, Huntington's chorea, Parkinson's        disease, peripheral neuropathies,    -   loss of hearing,    -   osteoporosis,    -   muscular dystrophies,    -   proliferative diseases such as for example atherosclerosis or        recurrence of stenosis,    -   cataract,    -   organ transplants,    -   auto-immune and viral diseases such as for example lupus, AIDS,        parasitic and viral infections, diabetes and its complications,        multiple sclerosis,    -   cancer,    -   all pathologies characterized by an excessive production of        ROS's and/or calpain activation.

In all these pathologies, there is experimental evidence demonstratingthe involvement of ROS's (Free Radic. Biol. Med. (1996) 20, 675-705;Antioxid. Health. Dis. (1997) 4 (Handbook of Synthetic-Antioxidants),1-52) as well as the involvement of calpains (Trends Pharmacol. Sci.(1994) 15, 412419; Drug News Perspect (1999) 12, 73-82). As an example,cerebral lesions associated with cerebral infarctions or withexperimental cranial traumatism are reduced by antioxidant agents (Acta.Physiol. Scand. (1994) 152, 349-350; J. Cereb. Blood Flow Metabol.(1995) 15, 948-952; J Pharmacol Exp Ther (1997) 2, 895-904) as well asby calpain inhibitors (Proc Natl Acad Sci USA (1996) 93, 3428-33;Stroke, (1998) 29, 152-158; Stroke (1994) 25, 2265-2270).

The Applicant had already described in the patent application PCT WO01/32654 heterocyclic compounds having at the same time a calpaininhibiting activity and an activity which traps reactive forms ofoxygen.

Said heterocyclic compounds of said patent application correspond togeneral formula (A1)

in which

R¹ represents a hydrogen atom, an —OR³, —SR³, oxo or a cyclic acetalradical,

-   -   in which R³ represents a hydrogen atom, an alkyl, arylalkyl,        heterocycloalkylcarbonyl, alkylcarbonyl, arylcarbonyl or        aralkylcarbonyl radical,    -   in which the alkyl, aryl or heterocycloalkyl radicals are        optionally substituted by one or more identical or different        substituents chosen from: alkyl, OH, alkoxy, nitro, cyano,        halogen or —NR⁴R⁵;    -   R⁴ and R⁵ represent, independently, a hydrogen atom or an alkyl        radical, or R⁴ and R⁵ form together with the nitrogen atom to        which they are attached an optionally substituted heterocycle,

R² represents a hydrogen atom, an alkyl, aryl or aralkyl radical, thearyl group being optionally substituted by one or more identical ordifferent radicals chosen from: —OR⁶, —NR⁷R⁸, halogen, cyano, nitro oralkyl,

-   -   in which R⁶, R⁷ and R⁸ represent, independently, a hydrogen        atom, an alkyl, aryl, aralkyl, alkylcarbonyl, arylcarbonyl or        aralkylcarbonyl radical;

A represents in particular an optionally substituted phenothiazinylradical;

X represents —(CH₂)_(n)—, —(CH₂)_(n)—CO—, —N(R⁴⁵)—CO—(CH₂)_(n)—CO—,—N(R⁴⁵)—CO-D-CO—, —CO—N(R⁴⁵)-D-CO—, —CO-D-CO—, —CH═CH—(CH₂)_(n)—CO—,—N(R⁴⁵)—(CH₂)_(n)—CO—, —N(R⁴⁵)—CO—C(R⁴⁶R⁴⁷)—CO—, —O—(CH₂)_(n)—CO—,—N(R⁴⁵)—CO—NH—C(R⁴⁶R⁴⁷)—CO—, —CO—N(R⁴⁵)—C(R⁴⁶R⁴⁷)—CO—, —S—(CH₂)_(n)—CO—or -Z-CO—;

D represents an optionally substituted phenylene radical;

Z represents a heterocycle,

R⁴⁵ represents a hydrogen atom or an alkyl radical,

R⁴⁶ and R⁴⁷ represent, independently, a hydrogen atom, an alkyl, aryl oraralkyl radical the alkyl and aryl groups of which are optionallysubstituted;

R⁴⁸ and R⁴⁹ represent, independently, a hydrogen atom, an alkyl radicalor a —COR⁵⁰ group, or R⁴⁸ and R⁴⁹ form together with the nitrogen atomto which they are attached an optionally substituted heterocycle,

R⁵⁰ represents a hydrogen atom, an alkyl, alkoxy or NR⁵¹R⁵² radical,

R⁵¹ and R⁵² represent, independently, a hydrogen atom or an alkylradical, or R⁵¹ and R⁵² form together with the nitrogen atom to whichthey are attached, an optionally substituted heterocycle;

n being an integer comprised between 0 and 6;

Y represents —(CH₂)_(p)—, —C(R⁵³R⁵⁴)—(CH₂)_(p)—, —C(R⁵³R⁵⁴)—CO—;

R⁵³ and R⁵⁴ represent, independently, a hydrogen atom, an alkyl radical,an aralkyl radical the aryl group of which is optionally substituted byone or more identical or different substituents chosen from: the OH,halogen, nitro, alkyl, alkoxy, —NR⁵⁵R⁵⁶ group,

R⁵⁵ and R⁵⁶ represent, independently, a hydrogen atom, an alkyl radicalor a —COR⁵⁷ group, or R⁵⁵ and R⁵⁶ form together with the nitrogen atomto which they are attached, an optionally substituted heterocycle,

R⁵⁷ represents a hydrogen atom, an alkyl, alkoxy or —NR⁵⁸R⁵⁹ radical,

R⁵⁸ and R⁵⁹ represent, independently, a hydrogen atom or an alkylradical, or R⁵⁸ and R⁵⁹ form together with the nitrogen atom to whichthey are attached an optionally substituted heterocycle;

p being an integer comprised between 0 and 6;

Het represents a heterocycle,

as well as the addition salts with mineral and organic acids or withmineral and organic bases of said compounds of general formula (A1),

with the exception of the compounds of formula (A1) in which when Hetrepresents tetrahydrofuran or tetrahydropyran, R¹ the OR³ radical withR³ representing a hydrogen atom, an alkyl, arylalkyl,heterocycloalkylcarbonyl radical the heterocycloalkyl radical of whichis branched by a carbon atom, alkylcarbonyl, arylcarbonyl oraralkylcarbonyl, R² a hydrogen and Y the —(CH₂)_(p)— radical with p=0,then X does not represent —CO—N(R⁴⁵)—C(R⁴⁶R⁴⁷)—CO— with R⁴⁵═R⁴⁶═H.

The Applicant has now surprisingly found that the compounds of generalformula (I) described hereafter have at the same time a calpaininhibiting activity and an activity which traps the reactive oxygenspecies whilst possessing improved properties in terms of cellpenetration.

A subject of the present invention is therefore the compounds of generalformula (I)

in which: _

A represents the

radical in which

R¹, R², R⁴, R⁵ and R⁶ represent, independently, a hydrogen atom, ahalogen atom, the OH group, an alkyl, alkoxy, cyano, nitro or NR⁷R⁸radical,

R⁷ and R⁸ represent, independently, a hydrogen atom, an alkyl radical ora —COR⁹ group,

R⁹ represents a hydrogen atom, an alkyl or alkoxy radical,

R³ represents a hydrogen atom, an alkyl radical or a —COR¹⁰ group,

R¹⁰ represents a hydrogen atom or an alkyl or alkoxy radical, and

W represents a bond or a —CH₂—CH₂—, —CH═CH—, —O—, —S— or —NR¹¹— radicalin which

R¹² represents a hydrogen atom or an alkyl radical;

X represents —CO—, —Y—CO—, —O—Y—CO— or —NR¹²—Y—CO—,

Y represents an alkylene or haloalkylene radical,

R¹² represents a hydrogen atom, an alkyl radical or a —COR¹³ group,

R¹³ represents a hydrogen atom, an alkyl, haloalkyl or alkoxy radical,

AA represents, each time that it occurs, a natural amino acid, a naturalamino acid the side chain of which carries a reactive chemical function(such as carboxylic acid, amine, alcohol or thiol) is protected in theform of alkyl or aralkyl ester (for the acid functions), alkyl oraralkyl carbamate or alkyl or aralkyl carboxamide (for the aminefunctions), in the form of alkyl or aralkyl ether or alkyl or aralkylthioether or in the form of alkyl or aralkyl ester (for the alcohol andthiol functions) or finally an amino acid of general formula—NR¹⁴—(CH₂)_(p)—CR¹⁵R¹⁶—CO— in which p represents 0 or 1, R¹⁴ representsa hydrogen atom or an alkyl radical, R¹⁵ represents a hydrogen atom oran alkyl radical and R¹⁶ a hydrogen atom, an alkyl, haloalkyl, phenyl,cycloalkyl, cycloalkylalkyl or alkenyl radical,

or R¹⁵ and R¹⁶ forming with the carbon atom to which they are attached asaturated carbocycle with 3 to 7 carbon atoms (and preferably with 3 to6 carbon atoms),

an -(AA)₂- group also being able to represent a carbapeptide of generalformula —NR¹⁷—(CH₂)₃—CH(R¹⁸)—CO— in which R¹⁷ represents a hydrogen atomor an alkyl radical and R¹⁸ represents a hydrogen atom or an alkylradical;

n represents 2 or 3; and finally

R represents a hydrogen atom or an alkyl or —CO—R¹⁹ radical in which R¹⁹represents an alkyl radical (and in particular methyl);

or the salts of such compounds.

By alkyl or alkylene, unless otherwise specified, is meant a linear orbranched alkyl or alkylene radical containing 1 to 12 carbon atoms, andpreferably 1 to 6 carbon atoms. By haloalkyl or haloalkylene is meant analkyl or alkylene radical at least one of the hydrogen atoms of which issubstituted by a halogen atom. By alkenyl, unless otherwise specified,is meant a linear or branched alkenyl radical containing 2 to 12 carbonatoms, and preferably 2 to 6 carbon atoms. By cycloalkyl, unlessotherwise specified, is meant a cycloalkyl radical containing 3 to 7carbon atoms. By alkoxy, unless otherwise specified, is meant an alkoxyradical the carbon chain of which is linear or branched and contains 1to 6 carbon atoms. By aryl, unless otherwise specified, is meant acarbocyclic aryl radical. By carbocyclic aryl is meant a carbocyclicaryl radical comprising 1 to 3 fused rings. Finally, by halogen atom ismeant an atom chosen from the fluorine, chlorine, bromine and iodineatoms.

By the aralkyl and cycloalkylalkyl radicals is meant respectively thearalkyl and cycloalkylalkyl radicals the alkyl, aryl and cycloalkylradicals of which, which constitute them, have the meanings previouslyindicated.

By natural amino acid is meant valine (Val), leucine (Leu), isoleucine(Ile), methionine (Met), phenylalanine (Phe), asparagine (Asn), glutamicacid (Glu), glutamine (Gln), histidine (His), lysine (Lys), arginine(Arg), aspartic acid (Asp), glycine (Gly), alanine (Ala), serine (Ser),threonine (Thr), tyrosine (Tyr), tryptophan (Trp), cysteine (Cys) orproline (Pro).

By linear or branched alkyl having 1 to 6 carbon atoms is meant inparticular the methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl and tert-butyl, pentyl, neopentyl, isopentyl, hexyl, isohexylradicals. By cycloalkyl containing 3 to 7 carbon atoms is meant inparticular a cyclohexyl radical. By carbocyclic aryl is meant inparticular the phenyl, naphthyl and phenantryl radicals, preferably thephenyl and naphthyl radicals and more preferentially the phenyl radical.By haloalkyl is meant in particular the —CF₃ radical. Finally, byhaloalkylene is meant in particular the —CF₂— radical.

Examples of protected functions carried by side chains of natural aminoacids include in particular:

-   -   protected acid functions in the form of methyl, ethyl,        tert-butyl or benzyl ester;    -   protected amine functions in the form of tert-butyl or benzyl        carbamate, acetamide;    -   protected alcohol functions in the form of tert-butyl, benzyl        ether or pyran or also in the form of acetyl; and    -   protected thiol functions in the form of methyl thioethers or in        the form of methyl thioesters.

Preferably, the compounds of the invention are such that they possess atleast one of the following characteristics:

R¹, R², R⁴, R⁵ and R⁶ represent, independently, a hydrogen atom, ahalogen atom or an alkyl, alkoxy or NR⁷R⁸ radical;

R³ represents a hydrogen atom, a methyl radical or a —COR⁹ radical inwhich R⁹ represents a methyl or tert-butoxy radical;

W represents a bond or a —CH₂—CH₂—, —CH═CH—, —O— or —S— radical;

X represents —CO—, —Y—CO— or —O—Y—CO—;

-(AA)_(n)- contains amino acids chosen independently from the groupconstituted by the natural amino acids, 3-methylvaline, norvaline,phenylglycine, vinylglycine and 2-aminobutyric acid;

n represents 2;

R represents a hydrogen atom or a methyl radical.

More preferentially, the compounds of the invention are such that theypossess at least one of the following characteristics:

R¹, R², R⁴, R⁵ and R⁶ represent, independently, a hydrogen atom or analkyl or alkoxy radical (and, still more preferentially, R¹, R², R⁴, R⁵and R⁶ are all hydrogen atoms);

R³ represents a hydrogen atom or a methyl radical (and, still morepreferentially, a hydrogen atom);

W represents —S—;

X represents —Y—CO— or —O—Y—CO—;

-(AA)_(n)- represents an -(AA²)-(AA¹)- group such that AA¹ representsLeu and AA² represents an amino acid chosen from the group constitutedby the natural amino acids, 3-methylvaline, norvaline, phenylglycine,vinylglycine and 2-aminobutyric acid (and, still more preferentially, an-(AA²)-(AA¹)- group such that AA¹ represents Leu and AA² represents anamino acid chosen from the group constituted by Leu, Lys, Val,3-methylvaline, norvaline, phenylglycine, vinylglycine and2-aminobutyric acid);

R represents a hydrogen atom.

In particular, the invention relates to a compound of general formula(I) chosen from the following compounds:

-   N-(10H-phenothiazin-2-ylcarbonyl)-L-leucyl-L-leucyl-N¹-[(3    S)-2-methoxytetrahydrofuran-3-yl]-L-leucinamide;-   N-(10H-phenothiazin-2-ylcarbonyl)-L-leucyl-L-leucyl-N¹-[(3S)-2-hydroxytetrahydrofuran-3-yl]-L-leucinamide;-   N-(10H-phenothiazin-2-ylcarbonyl)glycyl-N¹-[(3S)-2-methoxytetrahydrofuran-3-yl]-L-leucinamide;-   N-(10H-phenothiazin-2-ylcarbonyl)leucyl-N¹-[(3S)-2-methoxytetrahydrofuran-3-yl]-L-leucinamide;-   N⁶-[(benzyloxy)carbonyl]-N²-(10H-phenothiazin-2-ylcarbonyl)lysyl-N¹-[(3S)-2-methoxytetrahydrofuran-3-yl]-L-leucinamide;-   1-(10H-phenothiazin-2-ylcarbonyl)-L-prolyl-N¹-[(3    S)-2-methoxytetrahydrofuran-3-yl]-L-leucinamide;-   N-(10H-phenothiazin-2-ylcarbonyl)glycyl-N¹-[(3S)-2-hydroxytetrahydrofuran-3-yl]-L-leucinamide;-   N-(10H-phenothiazin-2-ylcarbonyl)leucyl-N¹-[(3S)-2-hydroxytetrahydrofuran-3-yl]-L-leucinamide;-   N⁶-[(benzyloxy)carbonyl]-N²-(10H-phenothiazin-2-ylcarbonyl)lysyl-N¹-[(3S)-2-hydroxytetrahydrofuran-3-yl]-L-leucinamide;-   1-(10H-phenothiazin-2-ylcarbonyl)-L-prolyl-N¹-[(3S)-2-hydroxytetrahydrofuran-3-yl]-L-leucinamide;-   N-(10H-phenothiazin-2-ylcarbonyl)leucyl-N¹-[(3S)-2-(acetyloxy)-tetrahydrofuran-3-yl]-L-leucinamide;-   N²-(10H-phenothiazin-2-ylcarbonyl)lysyl-N¹-[(3S)-2-hydroxytetrahydrofuran-3-yl]-L-leucinamide;-   N-(10H-phenothiazin-2-ylacetyl)-L-leucyl-N¹-[(3S)-2-methoxytetrahydrofuran-3-yl]-L-leucinamide;-   O-(tert-butyl)-N-(10H-phenothiazin-2-ylacetyl)-L-seryl-N¹-[(3S)-2-methoxytetrahydrofuran-3-yl]-L-leucinamide;-   N-(10H-phenothiazin-2-ylacetyl)-L-alanyl-3-cyclohexyl-N¹-[(3S)-2-methoxytetrahydrofuran-3-yl]-L-alaninamide;-   N-(10H-phenothiazin-2-ylacetyl)-L-leucyl-N¹-[(3S)-2-hydroxytetrahydrofuran-3-yl]-L-leucinamide;-   O-(tert-butyl)-N-(10H-phenothiazin-2-ylacetyl)-L-seryl-N¹-[(3S)-2-hydroxytetrahydrofiuran-3-yl]-L-leucinamide;-   N-(10H-phenothiazin-2-ylacetyl)-L-alanyl-3-cyclohexyl-N¹-[(3S)-2-hydroxytetrahydrofiuran-3-yl]-L-alaninamide;-   N-[3-(10H-phenothiazin-2-yl)propanoyl]-L-leucyl-N¹-[(3S)-2-methoxytetrahydrofuran-3-yl]-L-leucinamide;-   N-[3-(10H-phenothiazin-2-yl)propanoyl]-L-leucyl-N¹-[(3S)-2-hydroxytetrahydrofuran-3-yl]-L-leucinamide;-   N-[(10H-phenothiazin-2-yloxy)acetyl]-L-leucyl-N¹-[(3S)-2-methoxytetrahydrofuran-3-yl]-L-leucinamide;-   N-[(10H-phenothiazin-2-yloxy)acetyl]-glycyl-N¹-[(3S)-2-methoxytetrahydrofuran-3-yl]-L-leucinamide;-   N-[(10H-phenothiazin-2-yloxy)acetyl]-L-alanyl-N¹-[(3S)-2-methoxytetrahydrofuran-3-yl]-L-leucinamide;-   N-[(10H-phenothiazin-2-yloxy)acetyl]-L-valyl-N¹-[(3S)-2-methoxytetrahydrofuran-3-yl]-L-leucinamide;-   N-[(10H-phenothiazin-2-yloxy)acetyl]-13-alanyl-N¹-[(3S)-2-methoxytetrahydrofuran-3-yl]-L-leucinamide;-   N-methyl-N-[(10H-phenothiazin-2-yloxy)acetyl]glycyl-N¹-[(3    S)-2-methoxytetrahydrofuran-3-yl]-L-leucinamide;-   N-[(10H-phenothiazin-2-yloxy)acetyl]-D-valyl-N¹-[(3S)-2-methoxytetrahydrofuran-3-yl]-L-leucinamide;-   3-methyl-N-[(10H-phenothiazin-2-yloxy)acetyl]-L-valyl-N¹-[(3S)-2-methoxytetrahydrofuran-3-yl]-L-leucinamide;-   N¹-[(3S)-2-methoxytetrahydrofuran-3-yl]-N¹-((2S)-2-{[(10H-phenothiazin-2-yloxy)-acetyl]amino}butanoyl)-L-leucinamide;-   N-[(10H-phenothiazin-2-yloxy)acetyl]-L-norvalyl-N¹-[(3S)-2-methoxytetrahydrofuran-3-yl]-L-leucinamide;-   N-[(10H-phenothiazin-2-yloxy)acetyl]-L-seryl-N¹-[(3    S)-2-methoxytetrahydrofaran-3-yl]-L-leucinamide;-   N-[(10H-phenothiazin-2-yloxy)acetyl]-L-threonyl-N¹-[(3S)-2-methoxytetrahydrofuran-3-yl]-L-leucinamide;-   N¹-[(3S)-2-methoxytetrahydrofuran-3-yl]-N²-((2S)-2-{[(10H-phenothiazin-2-yloxy)acetyl]amino}-2-phenylethanoyl)-L-leucinamide;-   N¹-[(3S)-2-methoxytetrahydrofuran-3-yl]-N²-((2S)-2-{[(10H-phenothiazin-2-yloxy)acetyl]amino}but-3-enoyl)-L-leucinamide;-   2-methyl-N-[(10H-phenothiazin-2-yloxy)acetyl]alanyl-N¹-[(3S)-2-methoxytetrahydrofuran-3-yl]-L-leucinamide;-   N-[(10H-phenothiazin-2-yloxy)acetyl]-glycyl-N¹-[(3S)-2-methoxytetrahydrofuran-3-yl]-L-valinamide;-   N-[(10H-phenothiazin-2-yloxy)acetyl]-glycyl-3-cyclohexyl-N¹-[(3S)-2-methoxytetrahydrofuran-3-yl]-L-alaninamide;-   N-[(10H-phenothiazin-2-yloxy)acetyl]-glycyl-N-[(3S)-2-methoxytetrahydrofuran-3-yl]-L-phenylalaninamide;-   N-[(10H-phenothiazin-2-yloxy)acetyl]glycyl-N²-isobutyl-N¹-[(3S)-2-methoxytetrahydrofuran-3-yl]glycinamide;-   N-[(10H-phenothiazin-2-yloxy)acetyl]-L-leucyl-N¹-[(3S)-2-hydroxytetrahydrofuran-3-yl]-L-leucinamide;-   N-[(10H-phenothiazin-2-yloxy)acetyl]-glycyl-N¹-[(3    S)-2-hydroxytetrahydrofuran-3-yl]-L-leucinamide;-   N-[(10H-phenothiazin-2-yloxy)acetyl]-L-alanyl-N¹-[(3S)-2-hydroxytetrahydrofuran-3-yl]-L-leucinamide;-   N-[(10H-phenothiazin-2-yloxy)acetyl]-L-valyl-N¹-[(3    S)-2-hydroxytetrahydrofuran-3-yl]-L-leucinamide;-   N-[(10H-phenothiazin-2-yloxy)acetyl]-β-alanyl-N¹-[(3    S)-2-hydroxytetrahydrofuran-3-yl]-L-leucinamide;-   N-methyl-N-[(10H-phenothiazin-2-yloxy)acetyl]glycyl-N¹-[(3    S)-2-hydroxytetrahydrofuran-3-yl]-L-leucinamide;-   N-[(10H-phenothiazin-2-yloxy)acetyl]-D-valyl-N¹-[(3    S)-2-hydroxytetrahydrofuran-3-yl]-L-leucinamide;-   3-methyl-N-[(10H-phenothiazin-2-yloxy)acetyl]-L-valyl-N¹-[(3    S)-2-hydroxytetrahydrofuran-3-yl]-L-leucinamide;-   N¹-[(3    S)-2-hydroxytetrahydrofuran-3-yl]-N²-((2S)-2-{[(10H-phenothiazin-2-yloxy)acetyl]amino}butanoyl)-L-leucinamide;-   N-[(10H-phenothiazin-2-yloxy)acetyl]-L-norvalyl-N¹-[(3S)-2-hydroxytetrahydrofuran-3-yl]-L-leucinamide;-   N-[(10H-phenothiazin-2-yloxy)acetyl]-L-seryl-N¹-[(3S)-2-hydroxytetrahydrofuran-3-yl]-L-leucinamide;-   N-[(10H-phenothiazin-2-yloxy)acetyl]-L-threonyl-N¹-[(3    S)-2-hydroxytetrahydrofuran-3-yl]-L-leucinamide;-   N¹-[(3S)-2-hydroxytetrahydrofaran-3-yl]-N²-((2S)-2-{[(10H-phenothiazin-2-yloxy)acetyl]amino}-2-phenylethanoyl)-L-leucinamide;-   N¹-[(3S)-2-hydroxytetrahydrofuran-3-yl]-N²-((2S)-2-{[(10H-phenothiazin-2-yloxy)-acetyl]amino}but-3-enoyl)-L-leucinamide;-   2-methyl-N-[(10H-phenothiazin-2-yloxy)acetyl]alanyl-N¹-[(3S)-2-hydroxytetrahydrofuran-3-yl]-L-leucinamide;-   N-[(10H-phenothiazin-2-yloxy)acetyl]glycyl-N¹-[(3S)-2-hydroxytetrahydrofuran-3-yl]-L-valinamide;-   N-[(10H-phenothiazin-2-yloxy)acetyl]glycyl-3-cyclohexyl-N¹-[(3S)-2-hydroxytetrahydrofuran-3-yl]-L-alaninamide;-   N-[(10H-phenothiazin-2-yloxy)acetyl]glycyl-N-[(3S)-2-hydroxytetrahydrofuran-3-yl]-L-phenylalaninamide;-   N-[(10H-phenothiazin-2-yloxy)acetyl]glycyl-N¹-[(3S)-2-hydroxytetrahydrofuran-3-yl]-N²-isobutylglycinamide;-   N-[2-methyl-2-(10H-phenothiazin-2-yloxy)propanoyl]glycyl-N¹-[(3S)-2-methoxytetrahydrofuran-3-yl]-L-leucinamide;-   N-[2-methyl-2-(10H-phenothiazin-2-yloxy)propanoyl]glycyl-N¹-[(3S)-2-hydroxytetrahydrofuran-3-yl]-L-leucinamide;-   N-(10,11-dihydro-5H-dibenzo[b,f]azepin-3-ylcarbonyl)-L-leucyl-N¹-[(3S)-2-methoxytetrahydrofuran-3-yl]-L-leucinamide;-   N-(10,11-dihydro-5H-dibenzo[b,f]azepin-3-ylcarbonyl)-L-leucyl-N¹-[(3S)-2-hydroxytetrahydrofuran-3-yl]-L-leucinamide;-   N-[(5-acetyl-10,11-dihydro-5H-dibenzo[b,f]azepin-3-yl)carbonyl]-L-leucyl-N¹-[(3S)-2-methoxytetrahydrofuran-3-yl]-L-leucinamide;-   2-methyl-N-[(10H-phenothiazin-2-yloxy)acetyl]alanyl-N¹-[(3S)-2-hydroxytetrahydrofaran-3-yl]-L-leucinamide;-   or a salt of one of the latter.

A subject of the present invention is also, as medicaments, thecompounds of general formula (I) as defined previously, as well as thepharmaceutically acceptable salts of such compounds.

By pharmaceutically acceptable salt is meant in particular additionsalts of inorganic acids such as hydrochloride, hydrobromide,hydroiodide, sulphate, phosphate, diphosphate and nitrate or organicacids such as acetate, maleate, fumarate, tartrate, succinate, citrate,lactate, methanesulphonate, p-toluenesulphonate, pamoate and stearate.Also included within the scope of the present invention, when they canbe used, are the salts formed from bases such as sodium or potassiumhydroxide. For other examples of pharmaceutically acceptable salts,reference can be made to “Salt selection for basic drugs”, Int. J.Pharm. (1986), 33, 201-217.

The invention also relates to the pharmaceutical compositionscontaining, as active ingredient, a compound of general formula (I) asdefined previously, or a pharmaceutically acceptable salt of such acompound, with at least one pharmaceutically acceptable excipient.

The pharmaceutical compositions containing a compound of the inventioncan be in the form of a solid, for example powders, granules, tablets,gelatin capsules, liposomes, suppositories or patches. Appropriate solidsupports can be, for example, calcium phosphate, magnesium stearate,talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methylcellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine and wax.

The pharmaceutical compositions containing a compound of the inventioncan also be presented in liquid form, for example, solutions, emulsions,suspensions or syrups. Appropriate liquid supports can be, for example,water, organic solvents such as glycerol or the glycols, as well astheir mixtures, in varying proportions, in water.

The invention moreover relates to the use of a compound of generalformula (1) as defined previously, or of a pharmaceutically acceptablesalt of such a compound, for preparing a medicament intended to treatall the pathologies characterized by an excessive ROS production and/ora calpain activation, and in particular the diseases and disorderschosen from the group constituted by the inflammatory and immunologicaldiseases, cardio-vascular and cerebro-vascular diseases, disorders ofthe central or peripheral nervous system, osteoporosis, musculardystrophy, proliferative diseases, cataract, rejection reactionsfollowing organ transplants and autoimmune and viral diseases.

The administration of a medicament according to the invention can becarried out by topical route, oral route, parenteral route, byintramuscular injection, by subcutaneous injection, by intravenousinjection, etc.

The dose of a product according to the present invention, to be providedfor treatment of the abovementioned diseases or disorders, variesdepending on the administration method, the age and bodyweight of thesubject to be treated as well as the state of the latter, and will befinally decided by the attending doctor or vet. Such a quantitydetermined by the attending doctor or vet is here called the“therapeutically effective quantity”.

By way of indication, the administration dose envisaged for a medicamentaccording to the invention is comprised between 0.1 mg and 10 gdepending on the type of active ingredient used.

According to the invention, the compounds of general formula (1) can beprepared by the processes described hereafter.

Preparation of the Compounds of General Formula (I)

The compounds of formula (I) according to the invention can be preparedaccording to the synthesis route represented in Diagram 1 below (thecompounds of general formula (I) in which R represents an alkyl radicalAlk being called the compounds of general formula (I)₁, those of generalformula (I) in which R represents a hydrogen atom being called thecompounds of general formula (I)₂ and those of general formula (I) inwhich R represents —COR¹⁹ being called the compounds of general formula(I)₃ in the remainder of the specification):

The compounds of general formulae (I), and (I)₂ in which A, X, AA, n andR are as described previously are prepared, Diagram 1, by condensationof the acids of general formula (II) with the amines of general formula(III), under the standard conditions of peptide synthesis (M. Bodanszkyand A. Bodanszky, The Practice of Peptide Synthesis, 145(Springer-Verlag, 1984)) in THF, dichloromethane or DMF in the presenceof a coupling reagent such as dicyclohexylcarbodiimide (DCC),1,1′-carbonyldiimidazole (CDI) (J. Med. Chem. (1992), 35 (23),4464-4472) or 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (EDC or WSCI) (John Jones, The chemical synthesis ofpeptides, 54 (Clarendon Press, Oxford, 1991)) and of a base such as, forexample, triethylamine or N,N-diisopropylethylamine, in order to lead tothe compounds of general formula (II)₁. The hemiacetalic function of thecompounds of general formula (I)₁ can then be deprotected using anapproximately 2N aqueous solution of a mineral acid, such as forexample, HCl or HBr, using acetone as co-solvent. The lactol derivativesof general formula (I)₂ thus obtained can if appropriate be acylatedusing, in particular, an acid anhydride (R¹⁹CO)₂O (for example aceticanhydride) in the presence of an acylation agent such asN,N-dimethyl-4-pyridinamine in order to lead to the compounds of generalformula (I)₃.

Preparation of the Intermediates of General Formula (II):

The non-commercial carboxylic acids of general formula (II) in which A,W, X, Y, R¹, R², R³, R⁴, R⁵ and R⁶ are as described above, areaccessible according to different synthesis routes described in detailhereafter.

When X=—O—Y—CO—:

In this case, a synthesis route such as that represented in Diagram 2hereafter can be used.

According to this synthesis route, the acids of general formula (II) inwhich X represents —O—Y—CO—, Diagram 2, can be prepared from, forexample, hydroxy-phenothiazines (J. Med. Chem. (1992), 35(4), 716-24) orhydroxycarbazoles (J. Chem. Soc (1955), 3475-3477; J. Med. Chem. (1964),7, 158-161) of general formula (II.1). The condensation with commercialhalogenoesters of general formula (II.2) is carried out in the presenceof a base such as for example K₂CO₃ or Cs₂CO₃, by heating in a polarsolvent such as, for example, THF or DMF, for at least 5 hours. Theesters of general formula (II.3) obtained as intermediates are thendeprotected (in acid medium in the case of the tert-butyl esters or bysaponification for the methyl/ethyl esters) in order to lead to theacids of general formula (II) in which X represents the —O—Y—CO— group.

When X=—CO—:

In this case, synthesis routes such as those represented in Diagrams 3or 4 hereafter can if appropriate be used.

i) X represents —CO— and W represents —S—, —O— or a bond:

When X represents —CO— and W represents —S—, —O— or a bond, Diagram 3,the acid derivatives of phenothiazine or carbazole of general formula(II) can be obtained from 2-acetylphenothiazines (e.g. Pharmazie (1984),39(1), 22-3; Bull. Soc. Chim. (1968), (7), 2832-42, Pharmazie (1966),21(11), 645-9) or 2-acetylcarbazoles (e.g. Heterocycles (1994), 39(2),833-45; J. Indian Chem. Soc. (1985), 62(7), 534-6; J. Chem. Soc. Chem.Comm. (1985), (2), 86-7) of general formula (II.4) which areN-acetylated using acetyl chloride, by heating to reflux in toluene, inorder to lead to the intermediates (II.5) (J. Med. Chem. (1998), 41(2),148-156). The intermediates (II.5) thus obtained are successivelytreated by a mixture of iodine and pyridine (J. Amer. Chem. Soc. (1944),66, 894-895) and by aqueous soda, at 100° C., in order to lead to thecarboxylic acids of general formula (II).

ii) X represents —CO— and W represents —CH₂—CH₂— or —CH═CH—:

When X represents —CO— and W represents —CH₂—CH₂— or —CH═CH—, Diagram 4,the acids of general formula (II)_(Ac) or (II) can be prepared fromdi-acetylated derivatives of general formula (II.6) (e.g. J. Chem. Soc.(1973), 859-863). As in the case of the phenothiazines (Diagram 3), theoxidation of the acetyl is carried out using iodine and pyridinefollowed by hydrolysis in aqueous soda, while warm. The compounds ofgeneral formula (II)_(Ac) thus obtained (which are compounds of generalformula (II) in which R³ represents an acetyl group) can optionallyundergo additional treatment in the presence of aqueous potash, underreflux, for a time preferably comprised between 15 and 36 hours in orderto lead to the carboxylic acids of general formula (II).

When X=—Y—CO—:

For X=—Y—CO—, two synthetic routes represented in Diagram 5 hereaftermake it possible to access the carboxylic acids of general formula (II),according to the availability of the starting reagents.

In the case of the 2-acetylphenothiazines (W=—S—) or 2-acetylcarbazoles(W represents a bond) of general formula (II.4), described previously,the conversion to carboxylic acid of general formula (II) is carried out(left-hand part of Diagram 5) by a Willgerodt-Kindler-type homologationreaction (Synthesis (1975), 358-375). Heating of the intermediates ofgeneral formula (II.4) in the presence of sulphur and morpholine leadsto the formation of the thiocarboxamides of general formula (II.7)(German patent applications DE 2702714 and DE 1910291) which areconverted by hydrolysis to carboxylic acids of general formula (II).

Alternatively (right-hand part of Diagram 5), when W represents —S— or abond and m is an integer greater than 1, or when W represents —CH₂—CH₂—or —CH═CH— and m is an integer greater than or equal to 1, the synthesisof the carboxylic acids of general formula (II) starts with theacylation of the aromatic ring of the intermediates of general formula(II.8) by an alkanoyl chloride in CS₂, according to the Friedel-Craftsreaction conditions (J. Amer. Chem. Soc. (1946), 68, 2673-78; J. Chem.Soc. Perkin Trans. 1 (1973), 859-861). The acylated intermediates ofgeneral formula (11.9) are then converted to thiocarboxamide derivativesof general formula (II.10), by the Willgerodt-Kindler reaction, andfinally to carboxylic acids of general formula (II) according to thechemical sequence described previously.

Preparation of the Intermediates of General Formula (III):

The amino-lactol derivatives of general formula (III), in which AA, Rand n are as described above, are accessible using the preparation routerepresented in Diagram 6 hereafter. This process allows preparation ofthe compounds of general formula (III) in which n=2 (hereafter thecompounds of general formula (III)₂) and the compounds of generalformula (III) in which n=3 (hereafter the compounds of general formula(III)₃).

The amino-butyrolactone derivatives of general formula (III.2) areobtained by condensation of the protected amino acids of general formula(III.1), in which AA¹ is an amino acid radical AA as defined previouslyin general formula (I) and Gp is a protective group such as, forexample, a benzyl or tert-butyl carbamate, with (S)-α-aminobutyrolactoneunder the standard conditions of peptide synthesis in order to lead tothe carboxamide intermediates of general formula (III.2). The lactone isthen reduced to lactol using a reducing agent such as, for example,diisobutylaluminium hydride (DIBAL), in an inert solvent such as, forexample, THF or CH₂Cl₂, at a temperature preferably below −50° C., forexample at approximately −78° C. The hemiacetalic function of the lactolderivatives of general formula (III.3) is then protected in alcoholicmedium, for example in methanol, using a strong acid such as, forexample, trifluoroacetic acid, in order to lead to the acetals ofgeneral formula (III.4). The amine function of the amino-acetalderivatives of general formula (III.4) is then deprotected according tomethods described in the literature (T. W. Greene and P. G. M. Wuts,Protective Groups in Organic Synthesis, Second edition(Wiley-Interscience, 1991)). The intermediates of general formula(III.5) are then subjected to one or two successiveelongation-deprotection cycles of the peptide chain, as describedpreviously, in order to obtain the di- (n=2) or tri-peptidic (n=3)derivatives of respective general formulae (III)₂ and (III)₃.

In the particular case where the (AA²-AA¹) group or the (AA³-AA²) groupis replaced by a carbapeptide of general formula—NR¹⁷—(CH₂)₃—CH(R¹⁸)—CO—, the derivatives of general formula (III)₂ and(III)₃ can be obtained according to a peptide synthesis strategyanalogous to that described previously represented in Diagram 7hereafter (which only represents the situation where the (AA2-AA¹) groupis replaced by a carbapeptide—an analogous preparation process can beused for the case where the (AA³-AA²) group is replaced by acarbapeptide).

The carbapeptides of general formula (III.6) are themselves accessiblefrom processes described in the literature (e.g, Int. J. Peptide ProteinRes. (1992), 39, 273-277).

Unless otherwise specified, all the technical and scientific terms usedhere have the same meaning as that usually understood by an ordinaryspecialist in the field to which this invention belongs. Similarly, allthe publications, patent applications, all the patents and all otherreferences mentioned here are incorporated by way of reference.

The following examples are presented in order to illustrate the aboveprocedures and should in no case be considered as a limit to the scopeof the invention.

EXAMPLES Example 1N-(10H-phenothiazin-2-ylcarbonyl)-L-leucyl-L-leucyl-N¹-[(3S)-2-methoxytetrahydrofuran-3-yl]-L-leucinamide1.1)N²-[(benzyloxy)carbonyl]-N¹-[(3S)-2-oxotetrahydrofuran-3-yl]-L-leucinamide

3.51 g (13.25 mmol) of Cbz-L-Leucine, 2.41 g (1 eq.) of(S)-2-amino-4-butyrolactone hydrobromide, 1.97 g of HOBT (1.1 eq.) and5.59 g (2.2 eq.) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (EDC) is dissolved in 60 ml of anhydrous DMF then 7.64 ml(3.3 eq.) of N,N-diisopropylethylamine is added. The reaction mixture isstirred for 15 hours at 20° C. before being poured into 200 ml of a 1/1mixture of ethyl acetate/water. After stirring and decantation, theorganic solution is washed successively with 100 ml of a saturatedsolution of NaHCO₃, 50 ml of water, 100 ml of a 1 M solution of citricacid and finally 100 ml of a solution of salt water. The organic phaseis dried over sodium sulphate, filtered and concentrated to drynessunder vacuum. The oil obtained is washed using isopentane and thencrystallized from a dichloromethane/isopentane mixture. A white solid isobtained with a yield of 68%. Melting point: 130-131° C.

1.2)N²-[(benzyloxy)carbonyl]-N4-[(3S)-2-hydroxytetrahydrofuran-3-yl]-L-leucinamide

Under argon, in a three-necked-flask containing 60 ml-of anhydrousdichloromethane, 1.24 g (3.56 mmol) of intermediate 1.1 is dissolved.The mixture is cooled down to −60° C. before the addition, dropwise, of10.7 ml (3 eq.) of a 1M solution of DIBAL in dichloromethane. At the endof the addition, the cooling bath is removed and stirring is maintainedfor another 15 minutes. The reaction medium is then poured carefullyinto 100 ml of a 20% Rochelle salt solution. After vigorous stirring for2 hours, 100 ml of dichloromethane is added and the mixture is pouredinto a separating funnel. The organic phase is recovered and washed with50 ml of water and 50 ml of salt water. After drying over sodiumsulphate and filtration, the organic solution is concentrated to drynessunder vacuum. The evaporation residue is purified on a silica column(eluent: ethyl acetate/heptane in proportions of 1/1 to 8/2). A whitesolid is obtained with a yield of 72%. Melting point: 48-49° C.

1.3)N²-[(benzyloxy)carbonyl]-N4-[(3S)-2-methoxytetrahydrofuran-3-yl]-L-leucinamide

An excess of trifluoroacetic acid (5 ml) is added, dropwise at 20° C.,to a solution of 0.82 g (2.34 mmol) of intermediate 1.2 in 50 ml ofmethanol. Stirring is maintained for 15 hours at 20° C. The reactionmixture is then partially concentrated under vacuum and taken up in 50ml of dichloromethane. The organic solution is washed successively with50 ml of a saturated solution of NaHCO₃, 50 ml of water and 50 ml ofsalt water. After drying over sodium sulphate, filtration andconcentration under vacuum, the evaporation residue is purified on asilica column (eluent: ethyl acetate/heptane in proportions of 1/1 to7/3). A white solid is obtained with a yield of 80%. Melting point:112-113° C.

1.4) N¹-[(3S)-2-methoxytetrahydrofuran-3-yl]-L-leucinamide

2 g (5.5 mmol) of intermediate 1.3 and 600 mg of 10% Pd/C are introducedinto a stainless steel reactor containing 60 ml of methanol. The mixtureis stirred under 2 atm. of hydrogen pressure for 1 hour. Afterfiltration of the catalyst, the methanol is evaporated off under vacuum.The oily residue obtained (1.20 g; 94%) is used as it is in thefollowing stage.

1.5)N-[(benzyloxy)carbonyl]-L-leucyl-N4-[(3S)-2-methoxytetrahydrofuran-3-yl]-L-leucinamide

The experimental protocol used is the same as that described for thesynthesis of intermediate 1.1, intermediate 1.4 replacing(S)-2-amino-4-butyrolactone hydrobromide. The reaction product ispurified on a silica column (eluent: ethyl acetate/heptane 7/3). 1.04 gof a white solid is obtained with a yield of 69%. Melting point: 76-77°C.

1.6) L-leucyl-N¹-[(3S)-2-methoxytetrahydrofuran-3-yl]-L-leucinamide

The experimental protocol used is the same as that described for thesynthesis of intermediate 1.4, intermediate 1.5 replacing intermediate1.3. The reaction product is used without additional purification. 0.74g of a colourless foam is obtained with a yield of 96%.

1.7)N-[(benzyloxy)carbonyl]-L-leucyl-L-leucyl-N¹-[(3S)-2-methoxytetrahydrofuran-3-yl]-L-leucinamide

The experimental protocol used is the same as that described for thesynthesis of intermediate 1.1, intermediate 1.6 replacing(S)-2-amino-4-butyrolactone hydrobromide. The reaction product iscrystallized from an ethyl acetate/isopentane mixture. 0.96 g of a whitesolid is obtained with a yield of 77%. Melting point: 210-212° C.

1.8)L-leucyl-L-leucyl-N4-[(3S)-2-methoxytetrahydrofuran-3-yl]-L-leucinamide

The experimental protocol used is the same as that described for thesynthesis of intermediate 1.4, intermediate 1.7 replacing intermediate1.3. 0.74 g of a white solid is obtained with a quantitative yield.Melting point: 187-188° C.

1.9) 1-(10-acetyl-]10H-phenothiazin-2-yl)ethanone

30 g (0.118 mol) of 2-acetylphenothiazine and 9.28 g (1 eq.) of acetylchloride are introduced into a 500 ml flask containing 150 ml oftoluene. The reaction mixture is heated to reflux for 45 minutes beforethe introduction of a new portion of 4.6 g (0.5 eq.) of acetyl chloride.Stirring is maintained under heating at reflux for another 2 hours. Thereaction medium is then poured onto approximately 200 g of ice. Afterstirring, the organic phase is decanted and washed successively with 100ml of water and 100 ml of salt water. The organic solution is dried oversodium sulphate, filtered and concentrated to dryness using a rotaryevaporator. A yellow solid (33 g; 100%) is obtained which is used in thefollowing stage without additional purification.

1.10) 10H-phenothiazine-2-carboxylic acid

24 g (0.084 mol) of intermediate 1.9 is dissolved in 55 ml of pyridine.After the addition of 20.32 g (1 eq.) of iodine, the reaction mixture isheated at 100° C. for 15 minutes. Stirring is then maintained foranother 20 hours at 20° C. before concentration to dryness using arotary evaporator. 100 ml of water is added to the evaporation residuethus obtained, followed by 15 g (4.46 eq.) of NaOH in pellets. Thismixture is then heated at 100° C. for 1 hour. After cooling down usingan ice bath, the reaction mixture is washed with 100 ml of ethylacetate. The aqueous solution is then acidified using 50 ml of a 12Naqueous solution of HCl, an abundant precipitate appears. The latter isfiltered through a Büchner funnel, washed using ethanol and dried undervacuum at 75° C. An additional portion of the expected product can berecovered from the acid filtrate. The latter is extracted using twice100 ml of ethyl acetate. The organic phase is then washed with 50 ml ofwater followed by 50 ml of salt water. After drying over sodiumsulphate, the organic solution is concentrated to dryness under vacuum.The total quantity collected is 16.8 g in the form of a yellow solidwith a total yield of 82%. Melting point: >235° C.

1.11)N-(10H-phenothiazin-2-ylcarbonyl)-L-leucyl-L-leucyl-N¹-[(3S)-2-methoxytetrahydrofuran-3-yl]-L-leucinamide

The experimental protocol of this peptide condensation is the same asthat described for the synthesis of intermediate 1.1, this time using10H-phenothiazine-2-carboxylic acid (intermediate 1.10) andL-leucyl-L-leucyl-N¹-[(3S)-2-methoxytetrahydrofuran-3-yl]-L-leucinamide(intermediate 1.8). The reaction product is purified by chromatographyon silica (eluent: ethyl acetate/heptane in proportions of 7/3 to 1/1).228 mg of a yellow solid is obtained with a yield of 21%. Melting point:164-165° C.

Example 2N-(10H-phenothiazin-2-ylcarbonyl)-L-leucyl-L-leucyl-N¹-[(3S)-2-hydroxytetrahydrofuran-3-yl]-L-leucinamide

228 mg (0.33 mmol) of the compound of Example 1 is dissolved in a flaskcontaining 12 ml of acetone. 2 ml of a 2N aqueous solution of HCl isthen added dropwise at 20° C. Stirring is maintained for 6 hours 30minutes. The reaction medium is then concentrated to dryness and theevaporation residue is purified by chromatography on a silica column(eluent: ethyl acetate/heptane 9/1). 49 mg of a yellow solid is obtainedwith a yield of 22%. Melting point: 174-176° C.

The compounds of Examples 3 to 6 were prepared according to the samesynthesis strategy as that described for the compound of Example 1starting from intermediates 1.4, 1.6 and 1.10 and appropriate commercialprotected amino acids.

Example 3N-(10H-phenothiazin-2-ylcarbonyl)glycyl-N¹-[(3S)-2-methoxytetrahydrofuran-3-yl]-L-leucinamide

Yellow solid.

Example-4N-(10H-phenothiazin-2-ylcarbonyl)leucyl-N¹-[(3S)-2-methoxytetrahydrofuran-3-yl]-L-leucinamide

Yellow solid. Melting point: 180-180.5° C.

Example 5N⁶-[(benzyloxy)carbonyl]-N²-(10H-phenothiazin-2-ylcarbonyl)lysyl-N¹-[(3S)-2-methoxytetrahydrofuran-3-yl]-L-leucinamide

Yellow solid. Melting point: 102-103° C.

Example 61-(10H-phenothiazin-2-ylcarbonyl)-L-prolyl-N¹-[(3S)-2-methoxytetrahydrofuran-3-yl]-L-leucinamide

Yellow solid. Melting point: 243-243.5° C.

The compounds of Examples 7, 8, 9 and 10 were prepared according to theexperimental protocol described for the compound of Example 2 startingfrom the compounds of Examples 3, 4, 5 and 6 respectively.

Example 7N-(10H-phenothiazin-2-ylcarbonyl)glycyl-N¹-[(3S)-2-hydroxytetrahydrofuran-3-yl]-L-leucinamide

Yellow solid. Melting point: 126-126.5° C.

Example 8N-(10H-phenothiazin-2-ylcarbonyl)leucyl-N¹-[(3S)-2-hydroxytetrahydrofuran-3-yl]-L-leucinamide

Yellow-green solid. Melting point: 144-144.5° C.

Example 9N⁶-[(benzyloxy)carbonyl]-N²-(10H-phenothiazin-2-ylcarbonyl)lysyl-N¹-[(3S)-2-hydroxytetrahydrofuran-3-yl]-L-leucinamide

Yellow solid. Melting point: 109-109.5° C.

Example 101-(10H-phenothiazin-2-ylcarbonyl)-L-prolyl-N¹-[(3S)-2-hydroxytetrahydrofuran-3-yl]-L-leucinamide

Pale yellow solid. Melting point: 144.5-145° C.

Example 11N-(10H-phenothiazin-2-ylcarbonyl)leucyl-N¹-[(3S)-2-(acetyloxy)-tetrahydrofuran-3-yl]-L-leucinamide

0.62 ml (10 eq.) of acetic anhydride and 40 mg (0.5 eq.) of4-dimethylaminopyridine are added to a solution of 366 mg (0.66 mmol) ofthe compound of Example 8 in 6 ml of dichloromethane. The mixture isstirred for 4 hours at 20° C. The solution is then diluted with 20 ml ofdichloromethane and 20 ml of a saturated solution of NaHCO₃. Afterstirring and decantation, the organic phase is washed with 20 ml of saltwater. The organic solution is then dried over sodium sulphate, filteredand concentrated to dryness under vacuum. The evaporation residue ispurified on a silica column (eluent: heptane/AcOEt: 4/6 to 0/1). Thepure fractions are collected and concentrated under vacuum. The productis crystallized from a dichloromethane/isopentane mixture. The crystalsare filtered, rinsed with isopentane and dried. 180 mg of a pale yellowsolid is obtained with a yield of 56%. Melting point: 121-122° C.

Example 12N²-(10H-phenothiazin-2-ylcarbonyl)lysyl-N¹-[(3S)-2-hydroxytetrahydrofuran-3-yl]-L-leucinamidetrifluoroacetate

0.5 g (0.7 mmole) of the compound of Example 9 is dissolved in 5 ml ofacetic acid. After cooling down using an ice bath, 5 ml of an aqueous33% HBr solution is added dropwise. After stirring for 4 hours at 20°C., the reaction mixture is concentrated to dryness and the evaporationresidue is purified by preparative HPLC using a C18 column, 5 μm(eluent: THF/H₂O/TFA: 40/60/0.02). After lyophilization, 100 mg of abeige solid is obtained with a yield of 21%.

Example 13N-(10H-phenothiazin-2-ylacetyl)-L-leucyl-N¹-[(3S)-2-methoxytetrahydrofuran-3-yl]-L-leucinamide13.1) 2-(2-morpholin-4-yl-2-thioxoethyl)-10H-phenothiazine

The experimental protocol for the preparation of this intermediate isinspired by a synthesis described in the German patent application DE 2702 714. 24.13 g (0.1 mol) of 2-acetylphenothiazine, 5.13 g (1.6 eq.) ofsulphur and 39 ml (4.5 eq.) of morpholine are introduced into athree-necked flask equipped with a thermometer, a condenser and a gasoutlet immersing successively into a 2N soda trap and a trap of aconcentrated solution of potassium permanganate. The reaction mixture isheated to reflux (internal temperature=119° C.) for 15 hours. Aftercooling down, this brown solution is poured, under stirring, into 300 mlof absolute ethanol. The mixture is stored for 1 hour at 4° C. in orderto initiate crystallization and then overnight at −18° C. The solidobtained is then filtered and rinsed using cold ethanol and heptane.After drying, 27 g of an orange solid is obtained with a yield of 79%.

13.2) 10H-phenothiazin-2-ylacetic acid

31.23 g (91.2 mmol) of intermediate 13.1, 36 g (6 eq.) of 85% potash and350 ml of absolute ethanol are introduced into a three-necked flaskequipped as described previously. The reaction mixture is heated toreflux for 15 hours. After cooling down, this mixture is concentrated tohalf its volume under vacuum and then poured into 650 ml of water. Understirring, concentrated sulphuric acid is added to pH 1 and then themixture is taken to 80° C. After heating for 2 hours, the mixture iscooled down, the precipitate is filtered and rinsed with 4 times 40 mlof water. The solid thus obtained is dissolved in acetone and filteredin order to remove an insoluble solid. The filtrate is then concentratedto dryness under vacuum in order to lead to a pale yellow powder (15.67g) with a yield of 67%. Melting point: 201.5-202° C.

13.3)N-(10H-phenothiazin-2-ylacetyl)-L-leucyl-N4-[(3S)-2-methoxytetrahydrofuran-3-yl]-L-leucinamide

The experimental protocol used is the same as that described for Stage1.11 of Example 1, starting from intermediates 1.6 and 13.2. Beigesolid. Melting point: 216-216.5° C.

Example 14O-(tert-butyl)-N-(10H-phenothiazin-2-ylacetyl)-L-seryl-N¹-[(3S)-2-methoxytetrahydrofuran-3-yl]-L-leucinamide14.1)O-(tert-butyl)-L-seryl-N¹-[(3S)-2-methoxytetrahydrofuran-3-yl]-L-leucinamide

This intermediate was prepared in 2 stages according to the experimentalprotocols described for the synthesis of intermediates 1.5 and 1.6,starting from intermediate 1.4 and commercial Cbz-L-serine(tBu). Acolourless oil is obtained.

14.2)O-(tert-butyl)-N-(10H-phenothiazin-2-ylacetyl)-L-seryl-N¹-[(3S)-2-methoxytetrahydrofuran-3-yl]-L-leucinamide

The experimental protocol used is the same as that described for Stage1.11 of Example 1, from intermediates 14.1 and 13.2. White solid.Melting point: 179-180° C.

Example 15N-(10H-phenothiazin-2-ylacetyl)-L-alanyl-3-cyclohexyl-N¹-[(3S)-2-methoxytetrahydrofuran-3-yl]-L-alaninamide15.1) 3-cyclohexyl-N¹-[(3S)-2-methoxytetrahydrofuran-3-yl]-L-alaninamide

This intermediate was prepared in 4 stages according to the experimentalprotocols described for Stages 1.1 to 1.4 of Example 1, starting from(S)-2-amino-4-butyrolactone hydrobromide and commercialCbz-3-cyclohexyl-L-alanine. A colourless oil is obtained.

15.2)L-alanyl-3-cyclohexyl-N¹-[(3S)-2-methoxytetrahydrofuran-3-yl]-L-alaninamide

This intermediate was prepared in 2 stages according to the experimentalprotocols described for the synthesis of intermediates 1.5 and 1.6,starting from intermediate 15.1 and Cbz-L-alanine.

15.3)N-(10H-phenothiazin-2-ylacetyl)-L-alanyl-3-cyclohexyl-N¹-[(3S)-2-methoxytetrahydrofuran-3-yl]-L-alaninamide

The experimental protocol used is the same as that described for Stage1.11 of Example 1, starting from intermediates 15.2 and 13.2. A beigesolid is obtained. Melting point: 225-226° C.

The compounds of Examples 16, 17 and 18 were prepared according to theexperimental protocol described for the compound of Example 2 startingfrom the compounds of Examples 13, 14 and 15 respectively.

Example 16N-(10H-phenothiazin-2-ylacetyl)-L-leucyl-N¹-[(3S)-2-hydroxytetrahydrofuran-3-yl]-L-leucinamide

Beige solid. Melting point: 168-168.5° C.

Example 17O-(tert-butyl)-N-(10H-phenothiazin-2-ylacetyl)-L-seryl-N¹-[(3S)-2-hydroxytetrahydrofuran-3-yl]-L-leucinamide

Light beige solid. Melting point: 135-136° C.

Example 18N-(10H-phenothiazin-2-ylacetyl)-L-alanyl-3-cyclohexyl-N¹-[(3S)-2-hydroxytetrahydrofuran-3-yl]-L-alaninamide

White solid. Melting point: 215-217° C.

Example 19N-[3-(10H-phenothiazin-2-yl)propanoyl]-L-leucyl-N¹-[(3S)-2-methoxytetrahydrofuran-3-yl]-L-leucinamide19.1) 10-acetyl-10H-phenothiazine

20 g (0.1 mol) of phenothiazine followed by 14.3 ml (2 eq.) of acetylchloride are added to a 500 ml flask containing 200 ml of toluene. Theheterogeneous reaction mixture is stirred for 1 hour at 50° C. Afterconcentration to dryness, the precipitate is taken up in a minimum ofisopentane and filtered. After drying, 24 g of a beige solid is obtainedwith a quantitative yield. Melting point: 210-211° C.

19.2) 1-(10-acetyl-10H-phenothiazin-2-yl)propan-1-one

150 ml of CS₂ is introduced into a multi-necked flask equipped with amechanical stirrer, an argon supply, a condenser and an addition flask,followed by 24 g of intermediate 19.1. 10.4 ml (1.2 eq.) of propionylchloride is added, dropwise, to this vigorously-stirred suspension,followed by 50 g (4 eq.) of AlCl₃ in one portion, using a solid additionfunnel. The funnel is immediately rinsed with an additional 50 ml ofCS₂. Whilst stirring vigorously, the mixture is heated at 55° C. for 2hours. The mixture is then cooled down with an ice bath and the CS₂ iseliminated using a canula. The hydrolysis of the reaction mixture startsby the gradual addition of small pieces of ice and when the reaction isless virulent the hydrolysis is completed using cold water. The mixtureis finally diluted using 300 ml of ethyl acetate and transferred to aseparating funnel. The organic solution is decanted, washed twice with100 ml of water and 100 ml of salt water. After drying over sodiumsulphate, filtration and concentration to dryness under vacuum, theresidue obtained is triturated in isopentane. This solid is thenfiltered and rinsed with a minimum amount of isopentane. 13.2 g of awhite solid is obtained with a yield of 45%. Melting point: 146.5-147°C.

19.3) 3-(10H-phenothiazin-2-yl)propanoic acid

The experimental protocols used are the same as those described for thesyntheses of intermediates 13.1 and 13.2. 2 g of a brown solid isobtained from 6 g of intermediate 19.2, with a total yield (2 stages) of33%. This compound (80% purity) is used as it is in the following stage.

19.4)N-[3-(10H-phenothiazin-2-yl)propanoyl]-L-leucyl-N¹-[(3S)-2-methoxytetrahydrofuran-3-yl]-L-leucinamide

This example was prepared according to the same synthesis strategy asthat described for Stage 1.11 of Example 1 starting from intermediates1.6 and 19.3. Yellow solid. Melting point: 215-216° C.

Example 20N-[3-(10H-phenothiazin-2-yl)propanoyl]-L-leucyl-N¹-[(3S)-2-hydroxytetrahydrofuran-3-yl]-L-leucinamide

The experimental protocol used is the same as that described for thecompound of Example 2, starting with the compound of Example 19. Lightbeige solid. Melting point: 212-213° C.

Example 21N-[(10H-phenothiazin-2-yloxy)acetyl]-L-leucyl-N¹-[(3S)-2-methoxytetrahydrofuran-3-yl]-L-leucinamide21.1) 10H-phenothiazin-2-ol

A mixture of 25 g (109 mmol) of 2-methoxyphenothiazine and 60 g (4.8eq.) of pyridinium chloride is heated at 170° C. for 15 hours. Aftercooling down to a temperature of approximately 80° C., the brownsolution obtained is diluted with 200 ml of ethyl acetate. Stirring ismaintained for 30 minutes before pouring the reaction mixture into 200ml of water. After stirring and decantation, the organic phase is driedover sodium sulphate and concentrated to dryness, under vacuum. Thegreenish solid obtained is recrystallized from 700 ml of boilingtoluene. An insoluble solid is eliminated by filtration, the filtratecrystallizes spontaneously overnight. The crystals are collected byfiltration and rinsed using isopentane. After drying, 12.43 g of a greysolid is obtained with a yield of 53%. Melting point: 207-208° C.

21.2) tert-butyl (10H-phenothiazin-2-yloxy)acetate

In a 100 ml flask, 1 g (4.6 mmol) of intermediate 21.1 and 1.40 ml (2eq.) of tert-butyl bromoacetate are dissolved in 25 ml of THF. 1.93 g (3eq.) of K₂CO₃ is added to this solution and the reaction mixture isheated to reflux for 15 hours. After cooling down, 50 ml of water and 50ml of dichloromethane are added. The organic phase is decanted, washedwith 50 ml of water and 50 ml of salt water. After drying over sodiumsulphate, filtration and concentration under vacuum, the residueobtained is purified on a silica column, eluent ethyl acetate/heptane(2/8). 940 mg of a cream solid is obtained with a yield of 70%.

21.3) (10H-phenothiazin-2-yloxy)acetic acid

935 mg (2.8 mmol) of intermediate 21.2 is dissolved in 9 ml ofdichloromethane. The mixture is cooled down to 0° C. before theaddition, dropwise, of 2.19 ml (10 eq.) of trifluoroacetic acid. At theend of the addition, the temperature is allowed to return to 20° C. andstirring is maintained for 3 hours. The reaction mixture is thenconcentrated to dryness under vacuum and the residue rediluted with 50ml of ethyl acetate. The organic solution is washed with twice 25 ml ofwater followed by 25 ml of salt water. After drying over sodiumsulphate, filtration and concentration with a rotary evaporator, 540 mgof a pink solid is obtained with a yield of 69%. Melting point: 180-181°C.

21.4)N-[(10H-phenothiazin-2-yloxy)acetyl]-L-leucyl-N¹-[(3S)-2-methoxytetrahydrofuran-3-yl]-L-leucinamide

This example was prepared according to the same synthesis strategy asthat described for Stage 1.11 of Example 1 from intermediates 1.6 and21.3. Beige solid. Melting point: 211.5-212° C.

The compounds of Examples 22 to 35 were prepared according to the samesynthesis strategy as that described for the compound of Example Istarting from intermediates 1.4, 21.3 and the appropriate commercialprotected amino acids.

Example 22N-[(10H-phenothiazin-2-yloxy)acetyl]-glycyl-N¹-[(3S)-2-methoxytetrahydrofuran-3-yl]-L-leucinamide

Beige solid. Melting point: 181-182° C.

Example 23N-[(10H-phenothiazin-2-yloxy)acetyl]-L-alanyl-N¹-[(3S)-2-methoxytetrahydrofuran-3-yl]-L-leucinamide

White solid. Melting point: 195-196° C.

Example 24N¹-[(10H-phenothiazin-2-yloxy)acetyl]-L-valyl-N¹-[(3S)-2-methoxytetrahydrofuran-3-yl]-L-leucinamide

White solid. Melting point: 240-241° C.

Example 25N-[(10H-phenothiazin-2-yloxy)acetyl]-β-alanyl-N¹-[(3S)-2-methoxytetrahydrofuran-3-yl]-L-leucinamide

Brown solid. Melting point: 155-157° C.

Example 26N-methyl-N-[(10H-phenothiazin-2-yloxy)acetyl]glycyl-N¹-[(3S)-2-methoxytetrahydrofuran-3-yl]-L-leucinamide

Pale pink solid. Melting point: 92-95° C.

Example 27N-[(10H-phenothiazin-2-yloxy)acetyl]-D-valyl-N¹-[(3S)-2-methoxytetrahydrofuran-3-yl]-L-leucinamide

Light beige solid. Melting point: 204-206° C.

Example 283-methyl-N-[(10H-phenothiazin-2-yloxy)acetyl]-L-valyl-N¹-[(3S)-2-methoxytetrahydrofuran-3-yl]-L-leucinamide

Beige solid. Melting point: 152-153° C.

Example 29N¹-[(3S)-2-methoxytetrahydrofuran-3-yl]-N²-((2S)-2-{[(10H-phenothiazin-2-yloxy)-acetyl]amino}butanoyl)-L-leucinamide

Beige solid. Melting point: 164-165° C.

Example 30N-[(10H-phenothiazin-2-yloxy)acetyl]-L-norvalyl-N¹-[(3S)-2-methoxytetrahydrofuran-3-yl]-L-leucinamide

Beige solid. Melting point: 225-226° C.

Example 31N-[(10H-phenothiazin-2-yloxy)acetyl]-L-seryl-N¹-[(3S)-2-methoxytetrahydrofuran-3-yl]-L-leucinamide

Grey solid.

Example 32N-[(10H-phenothiazin-2-yloxy)acetyl]-L-threonyl-N¹-[(3S)-2-methoxytetrahydrofuran-3-yl]-L-leucinamide

Pale yellow solid. Melting point: 92-93° C.

Example 33N¹-[(3S)-2-methoxytetrahydrofuran-3-yl]-N¹-((2S)-2-{[(10H-phenothiazin-2-yloxy)acetyl]amino}-2-phenylethanoyl)-L-leucinamide

Pale yellow solid. Melting point: 215-217° C.

Example 34N¹-[(3S)-2-methoxytetrahydrofuran-3-yl]-N²-((2S)-2-{[(10H-phenothiazin-2-yloxy)acetyl]amino}but-3-enoyl)-L-leucinamide

Pale pink solid.

Example 352-methyl-N-[(10H-phenothiazin-2-yloxy)acetyl]alanyl-N¹-[(3S)-2-methoxytetrahydrofuran-3-yl]-L-leucinamide

Pale pink solid. Melting point: 119-120° C.

Example 36N-[(10H-phenothiazin-2-yloxy)acetyl]-glycyl-N¹-[(3S)-2-methoxytetrahydrofuran-3-yl]-L-valinamide36.1) N¹-[(3S)-2-methoxytetrahydrofuran-3-yl]-L-valinamide

This intermediate was prepared in 4 stages according to the experimentalprotocols described for Stages 1.1 to 1.4 of Example 1, using(S)-2-amino-4-butyrolactone hydrobromide and Cbz-L-valine. A colourlessoil is obtained.

36.2)N-[(10H-phenothiazin-2-yloxy)acetyl]-glycyl-N¹-[(3S)-2-methoxytetrahydrofuran-3-yl]-L-valinamide

This compound was prepared in 3 stages according to the experimentalprotocols described for Stages 1.5, 1.6 and 1.11 of Example 1 usingCbz-Glycine and intermediates 36.1 and 21.3. A beige solid is obtained.

Example 37N-[(10H-phenothiazin-2-yloxy)acetyl]-glycyl-3-cyclohexyl-N¹-[(3S)-2-methoxytetrahydrofuran-3-yl]-L-alaninamide

The synthesis strategy used is the same as that described for Stage 36.2of Example 36 using Cbz-Glycine and intermediates 15.1 and 21.3. A palepink solid is obtained. Melting point: 179-180° C.

Example 38N-[(10H-phenothiazin-2-yloxy)acetyl]-glycyl-N-[(3S)-2-methoxytetrahydrofuran-3-yl]-L-phenylalaninamide38.1) N-[(3S)-2-methoxytetrahydrofuran-3-yl]-L-phenylalaninamide

This intermediate was prepared in 4 stages according to the experimentalprotocols described for Stages 1.1 to 1.4 of Example 1, using(S)-2-amino-4-butyrolactone hydrobromide and Cbz-L-phenylalanine. Ayellow oil is obtained.

38.2)N-[(10H-phenothiazin-2-yloxy)acetyl]-glycyl-N-[(3S)-2-methoxytetrahydrofuran-3-yl-L-phenylalaninamide

The synthesis strategy used is the same as that described for Stage 36.2of Example 36 using Cbz-Glycine and intermediates 38.1 and 21.3. A beigesolid is obtained. Melting point: 203-204° C.

Example 39N-[(10H-phenothiazin-2-yloxy)acetyl]glycyl-N²-isobutyl-N¹-[(3S)-2-methoxytetrahydrofuran-3-yl]glycinamide39.1) N²-isobutyl-N¹-[(3S)-2-methoxytetrahydrofuran-3-yl]glycinamide

This intermediate was prepared in 4 stages according to the experimentalprotocols described for Stages 1.1 to 1.4 of Example 1, using(S)-2-amino-4-butyrolactone hydrobromide and Boc-N-isobutylglycine (J.Med. Chem. (2000), 43(15), 2805-2813). A colourless oil is obtained.

39.2)N-[(10H-phenothiazin-2-yloxy)acetyl]glycyl-N²-isobutyl-N¹-[(3S)-2-methoxytetrahydrofuran-3-yl]glycinamide

The synthesis strategy used is the same as that described for Stage 36.2of the example 36, using Cbz-Glycine and intermediates 39.1 and 21.3. Abeige solid is obtained. Melting point: 162-164° C.

The compounds of Examples 40 to 58 were prepared according to theexperimental protocol described for the compound of Example 2 startingfrom the compounds of Examples 21 to 39 respectively.

Example 40N-[(10H-phenothiazin-2-yloxy)acetyl]-L-leucyl-N¹-[(3S)-2-hydroxytetrahydrofuran-3-yl]-L-leucinamide

Light beige solid. Melting point: 141.5-142° C.

Example 41N-[(10H-phenothiazin-2-yloxy)acetyl]-glycyl-N¹-[(3S)-2-hydroxytetrahydrofuran-3-yl]-L-leucinamide

Pale pink solid. Melting point: 184-186° C.

Example 42N-[(10H-phenothiazin-2-yloxy)acetyl]-L-alanyl-N¹-[(3S)-2-hydroxytetrahydrofuran-3-yl]-L-leucinamide

Beige solid. Melting point: 144-146° C.

Example 43N-[(10H-phenothiazin-2-yloxy)acetyl]-L-valyl-N¹-[(3S)-2-hydroxytetrahydrofuran-3-yl]-L-leucinamide

White solid. Melting point: 205-206° C.

Example 44N-[(10H-phenothiazin-2-yloxy)acetyl]-p-alanyl-N¹-[(3S)-2-hydroxytetrahydrofuran-3-yl]-L-leucinamide

Pale pink solid. Melting point: 161-162° C.

Example 45N-methyl-N-[(10H-phenothiazin-2-yloxy)acetyl]glycyl-N¹-[(3S)-2-hydroxytetrahydrofuran-3-yl]-L-leucinamide

Light beige solid. Melting point: 137-138° C.

Example 46N-[(10H-phenothiazin-2-yloxy)acetyl]-D-valyl-N¹-[(3S)-2-hydroxytetrahydrofuran-3-yl]-L-leucinamide

White solid. Melting point: 145-146° C.

Example 473-methyl-N-[(10H-phenothiazin-2-yloxy)acetyl]-L-valyl-N¹-[(3S)-2-hydroxytetrahydrofuran-3-yl]-L-leucinamide

White solid. Melting point: 157-159° C.

Example 48N¹-[(3S)-2-hydroxytetrahydrofuran-3-yl]-N¹-((2S)-2-{1(10H-phenothiazin-2-yloxy)acetyl]amino}butanoyl)-L-leucinamide

Beige solid. Melting point: 160-161° C.

Example 49N-[(10H-phenothiazin-2-yloxy)acetyl]-L-norvalyl-N¹-[(3S)-2-hydroxytetrahydrofuran-3-yl]-L-leucinamide

Beige solid. Melting point: 195-196° C.

Example 50N-[(10H-phenothiazin-2-yloxy)acetyl]-L-seryl-N¹-[(3S)-2-hydroxytetrahydrofuran-3-yl]-L-leucinamide

Grey solid. Melting point: 128-130° C.

Example 51N-[(10H-phenothiazin-2-yloxy)acetyl]-L-threonyl-N¹-[(3S)-2-hydroxytetrahydrofuran-3-yl]-L-leucinamide

White solid. Melting point: 195-196° C.

Example 52N¹-[(3S)-2-hydroxytetrahydrofuran-3-yl]-N²-((2S)-2-{1[(10H-phenothiazin-2-yloxy)acetyl]amino}-2-phenylethanoyl)-L-leucinamide

White solid. Melting point: 137-138° C.

Example 53N¹-[(3S)-2-hydroxytetrahydrofuran-3-yl]-N²-((2S)-2-{[(10H-phenothiazin-2-yloxy)-acetyl]amino}but-3-enoyl)-L-leucinamide

Pale pink solid. Melting point: 159-161° C.

Example 542-methyl-N-[(10H-phenothiazin-2-yloxy)acetyl]alanyl-N¹-[(3S)-2-hydroxytetrahydrofuran-3-yl]-L-leucinamide

Beige solid. Melting point: 138-140° C.

Example 55N-[(10H-phenothiazin-2-yloxy)acetyl]glycyl-N¹-[(3S)-2-hydroxytetrahydrofuran-3-yl]-L-valinamide

Light beige solid. Melting point: 200-201° C.

Example 56N-[(10H-phenothiazin-2-yloxy)acetyl]glycyl-3-cyclohexyl-N¹-[(3S)-2-hydroxytetrahydrofuran-3-yl]-L-alaninamide

Pale pink solid. Melting point: 212-215° C.

Example 57N-[(10H-phenothiazin-2-yloxy)acetyl]glycyl-N-[(3S)-2-hydroxytetrahydrofuran-3-yl]-L-phenylalaninamide

Pale yellow solid. Melting point: 207-208° C.

Example 58N-1(10H-phenothiazin-2-yloxy)acetyl]glycyl-N¹-[(3S)-2-hydroxytetrahydrofuran-3-yl]-N-isobutylglycinamide

Pink solid. Melting point: 122-124° C.

Example 59N-[2-methyl-2-(10H-phenothiazin-2-yloxy)propanoyl]glycyl-N¹-[(3S)-2-methoxytetrahydrofuran-3-yl]-L-leucinamide59.1) tert-butyl 2-methyl-2-(10H-phenothiazin-2-yloxy)propanoate

1.93 g (3 eq.) of K₂CO₃ is added to a solution of 1 g (4.6 mmol) ofintermediate 21.1 in 10 ml of DMF. The reaction mixture was heated to60° C. before the addition of 1.73 ml (2 eq.) of tert-butyl2-bromoisobutyrate. The mixture is then taken to 110° C. and stirring ismaintained at this temperature for 6 hours. After returning to 20° C.,the mixture is poured into 100 ml of water and the product is extractedusing twice 100 ml of ethyl acetate. The organic solution is finallywashed with 100 ml of salt water, dried over sodium sulphate, filteredand concentrated to dryness under vacuum. The evaporation residue ispurified on a silica column, eluent: ethyl acetate/heptane (1/9). 450 mgof a pale pink solid is obtained with a yield of 28%. Melting point:138-140° C.

59.2) 2-methyl-2-(10H-phenothiazin-2-yloxy)propanoic acid

The experimental protocol used is the same as that described forintermediate 21.3, intermediate 59.1 replacing intermediate 21.2. 254 mgof a violet solid is obtained with a yield of 67%. Melting point:177-180° C.

59.3)N-[2-methyl-2-(10H-phenothiazin-2-yloxy)propanoyl/glycyl-N¹-[(3S)-2-methoxytetrahydrofuran-3-yl]-L-leucinamide

The synthesis strategy used is the same as that described for thesynthesis of the compound of Example 22, usingglycyl-N¹-[(3S)-2-methoxytetrahydrofuran-3-yl]-L-leucinamide (preparedin an analogous manner to intermediate 1.6) and intermediate 59.2. Paleyellow solid. Melting point: 100-104° C.

Example 60N-[2-methyl-2-(10H-phenothiazin-2-yloxy)propanoyl]glycyl-N¹-[(3S)-2-hydroxytetrahydrofuran-3-yl]-L-leucinamide

The experimental protocol is the same as that described for the compoundof Example 2, starting with the compound of Example 59 instead of thecompound of Example 1. A beige solid is obtained. Melting point:127-128° C.

Example 61N-(10,11-dihydro-5H-dibenzo[b,f]azepin-3-ylcarbonyl)-L-leucyl-N¹-[(3S)-2-methoxytetrahydrofuran-3-yl]-L-leucinamide61.1) 5-acetyl-10,11-dihydro-5H-dibenzo[b,f]azepine-3-carboxylic acid

The experimental protocol used is the same as that described for thesynthesis of intermediate 1.10, using1-(5-acetyl-10,11-dihydro-5H-dibenzo[b,f]azepin-3-yl)ethanone (J. Chem.Soc. 1973, 859-863) as starting product. A pale yellow solid is obtainedwith a yield of 62%. Melting point: 189-189.5° C.

61.2) 10,11-dihydro-5H-dibenzo[b,f]azepine-3-carboxylic acid

A mixture of 3.06 g (10.88 mmol) of intermediate 61.1 and 3 g (45 mmol)of KOH in 35 ml of ethanol is heated to reflux for 15 hours. Aftercooling down to 0° C., the reaction medium is acidified using 2N HCl topH=1. The mixture is then extracted using ethyl acetate then the organicsolution is washed with water, dried over sodium sulphate, filtered andfinally concentrated to dryness. A brown oil is obtained. Massspectrometry indicates 20% of the expected compound and 70% ofacetylated product (intermediate 61.1). The mixture is used as it is inthe following stage.

61.3)N-(10,11-dihydro-5H-dibenzo[b,f]azepin-3-ylcarbonyl)-L-leucyl-N′-[(3S)-2-methoxy-tetrahydrofuran-3-yl]-L-leucinamide

This compound was prepared according to the same synthesis strategy asthat described for the compound of Example 1, using intermediates 1.6and 61.2 as starting products.

Example 62N-(10,11-dihydro-5H-dibenzo[b,f]azepin-3-ylcarbonyl)-L-leucyl-N¹-[(3S)-2-hydroxytetrahydrofuran-3-yl]-L-leucinamide

The experimental protocol is the same as that described for the compoundof Example 2 using the compound of Example 61 as starting product. Alight beige solid is obtained. Melting point: 142-143° C.

Example 63N-[(5-acetyl-10,11-dihydro-5H-dibenzo[b,f]azepin-3-yl)carbonyl]-L-leucyl-N¹-[(3S)-2-methoxytetrahydrofuran-3-yl]-L-leucinamide

This compound was prepared according to the same synthesis strategy asthat described for the compound of Example 1, using intermediates 1.6and 61.1 as starting products.

Example 642-methyl-N-[(10H-phenothiazin-2-yloxy)acetyl]alanyl-N¹-[(3S)-2-hydroxytetrahydrofuran-3-yl]-L-leucinamide

The experimental protocol is the same as that described for Example 2,the compound of Example 63 replacing the compound of Example 1. A whitesolid is obtained. Melting point: 166-167° C.

Pharmacological Study of the compounds of the Invention:

Study of Effects on Human Calpain I

The test consists of measuring the activity of the enzyme (purifiedenzyme from human erythrocytes) which is incubated in a buffer in thepresence of a peptide substrate coupled to a fluorochrome(amino-methylcoumarin, AMC) and calcium. The enzyme activated by thecalcium proteolyzes the substrate and releases the AMC fragment. Thereleased AMC fluoresces at 460 nm under excitation at 380 nm. Theactivity of the enzyme is therefore proportional to the quantity offluorescence, i.e. free AMC fragment. The fluorescence (380/460 nm) ismeasured using a multi-well fluorometer (Victor 2, Wallac).

The assay is carried out in 96-well micro-plates with a transparent baseand black walls in which 10 μl per well of substance to be tested aredistributed, in 10% DMSO, 45 μl of reaction mixture containing humancalpain I at 2.2 U/ml (Calbiochem, ref: 208713), Suc Leu Tyr-AMCsubstrate (Bachem, ref: I-1355) at 1.1 mM in buffer (110 mM Tris-HCl;110 mM NaCl; 2.2 mM EDTA; 2.2 mM EGTA; 1.1 mM mercaptoethanol). Thereaction is initiated by adding 45 μl of 22 mM CaCl₂. In order todetermine the background noise, control wells without calcium are addedto the plate (10 μl 10% DMSO +45 μl of buffer with the enzyme and thesubstrate +45 μl H₂O). In order to determine the total activity of theenzyme, control wells without product are added to the plate (10 μL 10%DMSO +45 μl of buffer with the enzyme and the substrate +45 μl of 22 mMCaCl₂). Each concentration of the products (0.1 nM to 10 μM) is testedin duplicate. The plates are shaken and incubation takes place indarkness for one hour at 25° C. The fluorescence is read at 380/460 nmusing the fluorometer.

The compounds of Examples 2, 7 to 12, 16 to 18, 20, 40 to 53, 55 to 57,60, 62 and 64 have an IC₅₀ less than or equal to 5 μM in this test.

Study of the In Situ Effects on Calpain Activite in Rat (C6) Glial Cells

Rat C6 glial cells are seeded at 25,000 cells per well in 96-well platesin DMEM 10% FBS. The next day, the cells which have adhered are washed 3times in DMEM medium without serum and 40 mM Hepes. One hundredmicrolitres of the calpain inhibitor are deposited in the wells. Afterincubation for one hour at 37° C. under a 5% CO₂ atmosphere, 10 μlcontaining the fluorescent calpain substrate (Suc-Leu-Tyr-AMC) andmaitotoxin (Sigma, ref: M-9159), in order to obtain a finalconcentration in the well of 100 μM and 1 nM respectively, are added.

In order to determine the total activity of the cell enzyme, wellswithout product are added to the plate (100 μl DMSO 100^(th) plus 10 μlof MTX and substrate). The background noise is determined by addingcontrol wells without MTX. Each concentration of inhibitor (0.01 μM to100 μM) is tested in triplicate. The plates are shaken, the fluorescenceis read at 380/460 nm using Victor at T zero. Incubation took place forone hour thirty minutes for the C6 cells at 30° C. in darkness.

The compounds of Examples 8, 9, 11, 16, 20, 40, 43 and 47 to 53 have anIC₅₀ less than or equal to 10 μM in this test.

Study of the Effects on Lipid Peroxidation of Rat Cerebral Cortex

The inhibitory activity of the products of the invention is determinedby measuring their effects on the degree of lipid peroxidation,determined by the malondialdehyde (MDA) concentration. The MDA producedby the peroxidation of the unsaturated fatty acids is a good indicationof lipid peroxidation (H Esterbauer and K H Cheeseman, Meth. Enzymol.(1990), 186, 407-421). Male Sprague Dawley rats weighing 200 to 250 g(Charles River) were sacrificed by decapitation. The cerebral cortex isremoved, then homogenized using a Thomas potter in 20 mM Tris-HClbuffer, pH=7.4. The homogenate is centrifuged twice at 50,000 g for 10minutes at 4° C. The pellet is kept at −80° C. On the day of theexperiment, the pellet is replaced in suspension at a concentration of 1g/15 ml and centrifuged at 515 g for 10 minutes at 4° C. The supernatantis used immediately to determine the lipid peroxidation. The ratcerebral cortex homogenate (500 μl) is incubated at 37° C. for 15minutes in the presence of the compounds to be tested or solvent (10μl). The lipid peroxidation reaction is initiated by the addition of 50μl of 1 mM FeCl₂, 1 mM EDTA and 4 mM ascorbic acid. After incubation for30 minutes at 37° C., the reaction is stopped by the addition of 50 μlof a solution of di-tert-butyl hydroxyl toluene (BHT, 0.2%). The MDA isquantified using a colorimetric test, by reacting a chromogenic reagent(R), N-methyl-2-phenylindole (650 μl) with 200 μl of the homogenate for1 hour at 45° C. The condensation of an MDA molecule of with twomolecules of reagent R produces a stable chromophore the maximumabsorbance wavelength of which is equal to 586 nm. (Caldwell et al.,European J Pharmacol. (1995), 285, 203-206).

The compounds of Examples 2, 7 to 9, 11, 12, 16, 17, 20, 40 to 45, 56,57, 60 and 62 have an IC₅₀ less than or equal to 5 μM in this test.

1. A compound of the formula

wherein A is

R¹, R², R⁴, R⁵ and R⁶ are independently selected from the groupconsisting of hydrogen halogen OH alkyl, alkoxy, cyano, nitro and NR⁷R⁸,R⁷ and R⁸ are independently selected from the group consisting ofhydrogen alkyl and —COR⁹, R⁹ is selected from the group consisting ofhydrogen alkyl and alkoxy, R³ is selected from the group consisting ofhydrogen alkyl and —COR¹⁰, R¹⁰ is selected from the group consisting ofhydrogen alkyl and alkoxy, and W is selected from the group consistingof a bond, —CH₂—CH₂—, —CH═CH—, —O—, —S— and —NR¹¹— in which R¹¹ ishydrogen or alkyl; X is selected from the group consisting of —CO—,—Y—CO—, —O—Y—CO— and —NR¹²—Y—CO, Y is alkylene or haloalkylene, R¹² ishydrogen, alkyl and —COR¹³, R¹³ is selected from the group consisting ofhydrogen, alkyl, haloalkyl and alkoxy, AA is, each time that it occurs,selected from the group consisting of a natural amino acid, a naturalamino acid the side chain of which, which carries a reactive chemicalfunction, is protected in the form of alkyl or aralkyl ester (for theacid functions), alkyl or aralkyl carbamate or alkyl or aralkylcarboxamide in the form of alkyl or aralkyl ether or alkyl or aralkylthioether or in the form of alkyl or aralkyl ester (for the alcohol andthiol functions) and finally an amino acid of the formula—NR¹⁴—(CH₂)_(p)—CR¹⁵R¹⁶—CO— in which p is 0 or 1, R¹⁴ is hydrogen oralkyl, R¹⁵ is hydrogen or alkyl, R¹⁵ is hydrogen or alkyl, R¹⁵ ishydrogen or alkyl, R¹⁵ is hydrogen alkyl, haloalkyl, phenyl, cycloalkyl,cycloalkylalkyl and alkenyl, or R¹⁵ and R¹⁶ forming with the carbon atomto which they are attached a saturated carbocycle with 3 to 7 carbonatoms, an -(AA)₂- also being able to be a carbapeptide of the formula—NR¹⁷—(CH₂)₃—CH(R¹⁸)—CO— in which R¹⁷ is hydrogen or alkyl and R¹⁸ ishydrogen or alkyl; n is 2 or 3; and finally R is selected from the groupconsisting of hydrogen alkyl and —CO—R¹⁹ R¹⁹ is alkyl; and or a saltthereof.
 2. A compound of claim 1, wherein: R¹, R², R⁴, R⁵ and R⁶ areindependently selected from the group consisting of hydrogen, halogenalkyl, alkoxy an alkyl, alkoxy and —NR⁷R⁸; R³ is selected from the groupconsisting of hydrogen, methyl and —COR⁹ in which R⁹ is methyl ortert-butoxy; W is selected from the group consisting of a bond—CH₂—CH₂—, —CH═CH—, O and —S—; X is selected from the group consistingof —CO—, —Y—CO— and —O—Y—CO—; -(AA)_(n)- contains amino acids chosenindependently from the group consisting of natural amino acids,3-methylvaline, norvaline, phenylglycine, vinylglycine and2-aminobutyric acid; n is 2; and R is hydrogen or methyl; or a saltthereof.
 3. A compound of claim 1, wherein R¹, R², R⁴, R⁵ and R⁶ areindependently selected from the group consisting of hydrogen alkyl andalkoxy; R³ is hydrogen or methyl; W is —O— or —S—; X is —Y—CO— or—O—Y—CO—; -(AA)_(n)- is an -(AA²)-(AA¹)- such that AA¹ is Leu and AA² isan amino acid chosen from the group consisting of natural amino acids,3-methylvaline, norvaline, phenylglycine, vinylglycine and2-aminobutyric acid; R is hydrogen, or a salt thereof.
 4. A compound ofclaim 1 is selected from the group consisting of:N-(10H-phenothiazin-2-ylcarbonyl)-L-leucyl-L-leucyl-N¹-[(3S)-2-methoxytetrahydrofuran-3-yl]-L-leucinamide;N-(10H-phenothiazin-2-ylcarbonyl)-L-leucyl-L-leucyl-N¹-[(3S)-2-hydroxytetrahydrofuran-3-yl]-L-leucinamide;N-(10H-phenothiazin-2-ylcarbonyl)glycyl-N¹-[(3S)-2-methoxytetrahydrofuran-3-yl]-L-leucinamide;N-(10H-phenothiazin-2-ylcarbonyl)leucyl-N¹-[(3S)-2-methoxytetrahydrofuran-3-yl]-L-leucinamide;N⁶-[(benzyloxy)carbonyl]-N²-(10H-phenothiazin-2-ylcarbonyl)lysyl-N¹-[(3S)-2-methoxytetrahydrofuran-3-yl]-L-leucinamide;1-(10H-phenothiazin-2-ylcarbonyl)-L-prolyl-N¹-[(3S)-2-methoxytetrahydrofuran-3-yl]-L-leucinamide;N-(10H-phenothiazin-2-ylcarbonyl)glycyl-N¹-[(3S)-2-hydroxytetrahydrofuran-3-yl]-L-leucinamide;N-(10H-phenothiazin-2-ylcarbonyl)leucyl-N¹-[(3S)-2-hydroxytetrahydrofuran-3-yl]-L-leucinamide;N⁶-[(benzyloxy)carbonyl]-N²-(10H-phenothiazin-2-ylcarbonyl)lysyl-N¹-[(3S)-2-hydroxytetrahydrofuran-3-yl]-L-leucinamide;1-(10H-phenothiazin-2-ylcarbonyl)-L-prolyl-N¹-[(3S)-2-hydroxytetrahydrofuran-3-yl]-L-leucinamide;N-(10H-phenothiazin-2-ylcarbonyl)leucyl-N¹-[(3S)-2-(acetyloxy)-tetrahydrofuran-3-yl]-L-leucinamide;N²-(10H-phenothiazin-2-ylcarbonyl)lysyl-N¹-[(3S)-2-hydroxytetrahydrofuran-3-yl]-L-leucinamide;N-(10H-phenothiazin-2-ylacetyl)-L-leucyl-N¹-[(3S)-2-methoxytetrahydrofuran-3-yl]-L-leucinamide;O-(tert-butyl)-N-(10H-phenothiazin-2-ylacetyl)-L-seryl-N¹-[(3S)-2-methoxytetrahydrofuran-3-yl]-L-leucinamide;N-(10H-phenothiazin-2-ylacetyl)-L-alanyl-3-cyclohexyl-N¹-[(3S)-2-methoxytetrahydrofuran-3-yl]-L-alaninamide;N-(10H-phenothiazin-2-ylacetyl)-L-leucyl-N¹-[(3S)-2-hydroxytetrahydrofuran-3-yl]-L-leucinamide;O-(tert-butyl)-N-(10H-phenothiazin-2-ylacetyl)-L-seryl-N¹-[(3S)-2-hydroxytetrahydrofiuran-3-yl]-L-leucinamide;N-(10H-phenothiazin-2-ylacetyl)-L-alanyl-3-cyclohexyl-N¹-[(3S)-2-hydroxytetrahydrofiuran-3-yl]-L-alaninamide;N-[3-(10H-phenothiazin-2-yl)propanoyl]-L-leucyl-N¹-[(3S)-2-methoxytetrahydrofuran-3-yl]-L-leucinamide;N-[3-(10H-phenothiazin-2-yl)propanoyl]-L-leucyl-N¹-[(3S)-2-hydroxytetrahydrofuran-3-yl]-L-leucinamide;N-[(10H-phenothiazin-2-yloxy)acetyl]-L-leucyl-N¹-[(3S)-2-methoxytetrahydrofuran-3-yl]-L-leucinamide;N-[(10H-phenothiazin-2-yloxy)acetyl]-glycyl-N¹-[(3S)-2-methoxytetrahydrofuran-3-yl]-L-leucinamide;N-[(10H-phenothiazin-2-yloxy)acetyl]-L-alanyl-N¹-[(3S)-2-methoxytetrahydrofuran-3-yl]-L-leucinamide;N-[(10H-phenothiazin-2-yloxy)acetyl]-L-valyl-N¹-[(3S)-2-methoxytetrahydrofuran-3-yl]-L-leucinamide;N-[(10H-phenothiazin-2-yloxy)acetyl]-13-alanyl-N¹-[(3S)-2-methoxytetrahydrofuran-3-yl]-L-leucinamide;N-methyl-N-[(10H-phenothiazin-2-yloxy)acetyl]glycyl-N¹-[(3S)-2-methoxytetrahydrofuran-3-yl]-L-leucinamide;N-[(10H-phenothiazin-2-yloxy)acetyl]-D-valyl-N¹-[(3S)-2-methoxytetrahydrofuran-3-yl]-L-leucinamide;3-methyl-N-[(10H-phenothiazin-2-yloxy)acetyl]-L-valyl-N¹-[(3S)-2-methoxytetrahydrofuran-3-yl]-L-leucinamide;N¹-[(3S)-2-methoxytetrahydrofuran-3-yl]-N¹-((2S)-2-{[(10H-phenothiazin-2-yloxy)-acetyl]amino}butanoyl)-L-leucinamide;N-[(10H-phenothiazin-2-yloxy)acetyl]-L-norvalyl-N¹-[(3S)-2-methoxytetrahydrofuran-3-yl]-L-leucinamide;N-[(10H-phenothiazin-2-yloxy)acetyl]-L-seryl-N¹-[(3S)-2-methoxytetrahydrofaran-3-yl]-L-leucinamide;N-[(10H-phenothiazin-2-yloxy)acetyl]-L-threonyl-N¹-[(3S)-2-methoxytetrahydrofuran-3-yl]-L-leucinamide;N¹-[(3S)-2-methoxytetrahydrofuran-3-yl]-N²-((2S)-2-{[(10H-phenothiazin-2-yloxy)acetyl]amino}-2-phenylethanoyl)-L-leucinamide;N¹-[(3S)-2-methoxytetrahydrofuran-3-yl]-N²-((2S)-2-{[(10H-phenothiazin-2-yloxy)acetyl]amino}but-3-enoyl)-L-leucinamide;2-methyl-N-[(10H-phenothiazin-2-yloxy)acetyl]alanyl-N¹-[(3S)-2-methoxytetrahydrofuran-3-yl]-L-leucinamide;N-[(10H-phenothiazin-2-yloxy)acetyl]-glycyl-N¹-[(3S)-2-methoxytetrahydrofuran-3-yl]-L-valinamide;N-[(10H-phenothiazin-2-yloxy)acetyl]-glycyl-3-cyclohexyl-N¹-[(3S)-2-methoxytetrahydrofuran-3-yl]-L-alaninamide;N-[(10H-phenothiazin-2-yloxy)acetyl]-glycyl-N-[(3S)-2-methoxytetrahydrofuran-3-yl]-L-phenylalaninamide;N-[(10H-phenothiazin-2-yloxy)acetyl]glycyl-N²-isobutyl-N¹-[(3S)-2-methoxytetrahydrofuran-3-yl]glycinamide;N-[(10H-phenothiazin-2-yloxy)acetyl]-L-leucyl-N¹-[(3S)-2-hydroxytetrahydrofuran-3-yl]-L-leucinamide;N-[(10H-phenothiazin-2-yloxy)acetyl]-glycyl-N¹-[(3S)-2-hydroxytetrahydrofuran-3-yl]-L-leucinamide;N-[(10H-phenothiazin-2-yloxy)acetyl]-L-alanyl-N¹-[(3S)-2-hydroxytetrahydrofuran-3-yl]-L-leucinamide;N-[(10H-phenothiazin-2-yloxy)acetyl]-L-valyl-N¹-[(3S)-2-hydroxytetrahydrofuran-3-yl]-L-leucinamide;N-[(10H-phenothiazin-2-yloxy)acetyl]-β-alanyl-N¹-[(3S)-2-hydroxytetrahydrofuran-3-yl]-L-leucinamide;N-methyl-N-[(10H-phenothiazin-2-yloxy)acetyl]glycyl-N¹-[(3S)-2-hydroxytetrahydrofuran-3-yl]-L-leucinamide;N-[(10H-phenothiazin-2-yloxy)acetyl]-D-valyl-N¹-[(3S)-2-hydroxytetrahydrofuran-3-yl]-L-leucinamide;3-methyl-N-[(10H-phenothiazin-2-yloxy)acetyl]-L-valyl-N¹-[(3S)-2-hydroxytetrahydrofuran-3-yl]-L-leucinamide; N¹-[(3S)-2-hydroxytetrahydrofuran-3-yl]-N²-((2S)-2-{[(10H-phenothiazin-2-yloxy)acetyl]amino}butanoyl)-L-leucinamide;N-[(10H-phenothiazin-2-yloxy)acetyl]-L-norvalyl-N¹-[(3S)-2-hydroxytetrahydrofuran-3-yl]-L-leucinamide;N-[(10H-phenothiazin-2-yloxy)acetyl]-L-seryl-N¹-[(3S)-2-hydroxytetrahydrofuran-3-yl]-L-leucinamide;N-[(10H-phenothiazin-2-yloxy)acetyl]-L-threonyl-N¹-[(3S)-2-hydroxytetrahydrofuran-3-yl]-L-leucinamide;N¹-[(3S)-2-hydroxytetrahydrofaran-3-yl]-N²-((2S)-2-{[(10H-phenothiazin-2-yloxy)acetyl]amino}-2-phenylethanoyl)-L-leucinamide;N¹-[(3S)-2-hydroxytetrahydrofuran-3-yl]-N²-((2S)-2-{[(10H-phenothiazin-2-yloxy)-acetyl]amino}but-3-enoyl)-L-leucinamide;2-methyl-N-[(10H-phenothiazin-2-yloxy)acetyl]alanyl-N¹-[(3S)-2-hydroxytetrahydrofuran-3-yl]-L-leucinamide;N-[(10H-phenothiazin-2-yloxy)acetyl]glycyl-N¹-[(3S)-2-hydroxytetrahydrofuran-3-yl]-L-valinamide;N-[(10H-phenothiazin-2-yloxy)acetyl]glycyl-3-cyclohexyl-N¹-[(3S)-2-hydroxytetrahydrofuran-3-yl]-L-alaninamide;N-[(10H-phenothiazin-2-yloxy)acetyl]glycyl-N-[(3S)-2-hydroxytetrahydrofuran-3-yl]-L-phenylalaninamide;N-[(10H-phenothiazin-2-yloxy)acetyl]glycyl-N¹-[(3S)-2-hydroxytetrahydrofuran-3-yl]-N²-isobutylglycinamide;N-[2-methyl-2-(10H-phenothiazin-2-yloxy)propanoyl]glycyl-N¹-[(3S)-2-methoxytetrahydrofuran-3-yl]-L-leucinamide;N-[2-methyl-2-(10H-phenothiazin-2-yloxy)propanoyl]glycyl-N¹-[(3S)-2-hydroxytetrahydrofuran-3-yl]-L-leucinamide;N-(10,11-dihydro-5H-dibenzo[b,f]azepin-3-ylcarbonyl)-L-leucyl-N¹-[(3S)-2-methoxytetrahydrofuran-3-yl]-L-leucinamide;N-(10,11-dihydro-5H-dibenzo[b,f]azepin-3-ylcarbonyl)-L-leucyl-N¹-[(3S)-2-hydroxytetrahydrofuran-3-yl]-L-leucinamide;N-[(5-acetyl-10,11-dihydro-5H-dibenzo[b,f]azepin-3-yl)carbonyl]-L-leucyl-N¹-[(3S)-2-methoxytetrahydrofuran-3-yl]-L-leucinamide;2-methyl-N-[(10H-phenothiazin-2-yloxy)acetyl]alanyl-N¹-[(3S)-2-hydroxytetrahydrofaran-3-yl]-L-leucinamide;and or a salt thereof. 5-10. (canceled)
 11. A composition for inhibitingcalpains and lipid peroxidation comprising an inhibitorily effectiveamount of a compound of claim 1 and an inert pharmaceutical carrier. 12.A method of inhibiting calpains in warm-blooded animals comprisingadministering to warm-blooded animals in need thereof a calpaininhibitorily effective amount of a compound of claim
 1. 13. A method ofinhibiting lipid peroxidation in warm-blooded animals comprisingadministering to warm-blooded animals in need thereof a lipidperoxidation inhibitorily effective amount of a compound of claim
 1. 14.A method of treating a disorder selected from the group consisting ofinflammatory and immunological diseases, cardiovascular andcerebro-vascular diseases, disorders of the central or peripheralnervous system, osteoporosis, muscular dystrophy, proliferativediseases, cataract, rejection reactions following organ transplants andautoimmune and viral diseases.